Myoclonus

Etiology

Myoclonus can be a feature of myriad neurological diseases and disorders. Perhaps most pathognomonically associated with "startle myoclonus" in Creutzfeld-Jakob disease, myoclonus can also be a feature of neurodegenerative diseases like Alzheimer disease, dementia with Lewy bodies, Parkinson disease, frontotemporal dementia, and disorders of basal ganglia or spinocerebellar degeneration, among others. Inflammatory conditions—infectious, post-infectious, antibody-mediated, or paraneoplastic—often feature myoclonic jerks. Metabolic derangement, toxidromes, physical encephalopathy, focal neurological insults, trauma, and malabsorption all can, but do not invariably, cause myoclonus. A single disease (likewise, a single individual) may manifest more than a single subtype of myoclonus. 

The specific etiologic mechanisms underlying myoclonus remain poorly understood. At present, researchers theorize that myoclonus may emerge as a consequence of motor strip hyperexcitability, abnormalities or deficiencies in neurotransmitter receptors, imbalances between neurotransmitters, or underlying network abnormalities that have yet to be elucidated. An extensive list of possible etiologies follows, but a fully comprehensive list would be beyond the scope of this activity.

Myoclonus is a clinical sign rather than a disease. The array of underlying etiologies of myoclonus is strikingly diverse. It can be bewildering unless one has a structured and organized approach to diagnosis and clinical decision-making combining several (and overlapping) classification schemes. These schemes include 1) classification according to body distribution, 2) classification according to clinical presentation, and 3) classification based on results of neurophysiologic testing.[1]  Description of new classification schemes and emendation of currently operating ones continues, especially as research unveils unknown molecular genetic causes of myoclonus.[2] In all cases, the structured clinical approach aims to maximize the likelihood that all possible etiologies are explored. Classification of myoclonus according to etiology based on clinical presentation is frequently the preferred starting point for the ensuing workup.[3] 

The most basic distinction subdivides myoclonus into primary and secondary phenomena, as initially proposed by Marsden et al in the early 1980s and considerably expanded upon since then. Physiologic, essential, hereditary, and epileptic myoclonus are considered primary. Secondary myoclonus, also known as symptomatic myoclonus, occurs when myoclonus results from a comorbid primary medical or neurologic condition. Virtually all pathophysiologic processes can produce myoclonus as a sign, including inflammation, infectious diseases, paraneoplastic syndromes, structural lesions, side effects of substances (licit and illicit), metabolic derangement, and degenerative disorders. Indeed, a single individual or disease state can manifest more than just a single type of myoclonus.[3] 

Primary Myoclonus

Physiologic myoclonus

• Physiologic myoclonus is just that: physiologic. As such, it occurs as a normal phenomenon in almost everyone, albeit with considerable variability in prominence and frequency, even sometimes going entirely unnoticed by the affected individual.
• Startle responses and hiccups are examples of physiologic myoclonus that occur in most people at some point over the lifespan and, by way of treatment, usually require nothing more than explanation and reassurance.
• So, too, most myoclonic jerks occurring as part of sleep transitions (ie, hypnogogic jerks upon entering sleep) are considered physiologic. However, these jerks may disrupt restful sleep for the patient and the sleep partner, in which case treatment might be warranted. 

Essential myoclonus

• Essential myoclonus is a relatively isolated occurrence in which the myoclonus is the primary, and sometimes the only, symptom. Essential myoclonus tends to be either minimally or even entirely nonprogressive. By definition, other neurological systems are unaffected in essential myoclonus.[4] 
• The degree of dysfunction caused by essential myoclonus varies, and for some people, the myoclonus can interfere with coordination or become moderate enough to necessitate pharmacologic intervention. That said, many affected individuals can compensate with little or no difficulty. 
• Essential myoclonus can occur either sporadically, in which case the etiology is usually unexplained (idiopathic), or in a hereditary fashion, usually via autosomal dominant inheritance patterns.
• Myoclonus-dystonia (also known as hereditary essential myoclonus) describes an inherited disorder wherein repetitive and rhythmic myoclonic movements occur in the upper extremities; usually, either myoclonic or dystonic movements predominate, but both must be present for the diagnosis to be valid.
• Differentiating myoclonus-dystonia from essential tremor can be tricky, particularly since both conditions tend to respond well to judicious intake of alcohol.
• Several genetic mutations have been implicated, including mutations in the ε-Sarcoglycan gene (SGCE)[5].
• Psychiatric symptoms often occur and may be significant; one recent long-term follow-up study noted that prevalence may increase over time.[6] 
• Nonmovement neurologic systems are usually, but not invariably, uninvolved. 

Epileptic myoclonus

• Epileptic myoclonus refers to seizure disorders in which the myoclonus forms all or part of the ictus.
• Myoclonus may be the sole epileptic manifestation, one of several components in seizure semiology (herein known as a "seizure fragment"), or as one type of seizure in an epilepsy syndrome with multiple and overlapping seizure subtypes. 
• Examples of epileptic syndromes with myoclonic seizures include:
• Juvenile myoclonic epilepsy (JME): With onset usually during puberty, JME is a generalized epilepsy in which a myoclonic seizure produces the characteristic jerk. Classically described as occurring in the morning hours, myoclonic seizures occur unpredictably; the seizure threshold can be lowered by sleep deprivation, alcohol ingestion, and stress. Myoclonic seizures typically affect the upper arms, neck, and shoulders, but generalized tonic-clonic seizures (affecting the entire body) also occur commonly. 
• Progressive myoclonic epilepsy (PME): PME is a progressive and sometimes fatal disorder. PME is a relatively rare epileptic syndrome that includes myoclonic seizures in combination with other neurologic dysfunction, such as ataxia, rigidity, cognitive impairment, or aphasia. More than a dozen varieties of PME have been described; the underlying molecular genetic defects have been identified for Unverricht-Lundborg disease, Lafora body disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers (MERRF), and type 1 and 2 sialidoses. In most cases, the underlying genetic defect has autosomal recessive inheritance.[7]
• Lennox-Gastaut Syndrome (LGS): LGS describes a severe epilepsy syndrome with onset usually in infancy or early childhood. LGS is characterized by multiple and overlapping general seizure types (most commonly atonic, tonic, and atypical absence), a pathognomonic signature on electroencephalogram (EEG), cognitive dysfunction, and refractoriness to many anti-epileptic drugs. 
• Epilepsy with myoclonic atonic seizures (EMAS): EMAS is a rare epileptiform syndrome of early childhood, first described by Doose in 1970. EMAS is characterized by multiple types of generalized seizures, which are often followed by drop attacks that can cause falls and injuries. In some cases, persistent seizures do not respond to treatment, with resultant intellectual disability. In others, complete seizure remission can occur, often after several years and, in some cases, can lead to eventual normalization. Changes in the SCN1A, SCN1B, GABRG2, CHD2, and SLC6A1 genes have been identified in EMAS, although the syndrome is frequently idiopathic.

Secondary Myoclonus 

Secondary myoclonus is also known as symptomatic myoclonus. Recall that symptomatic myoclonus is a clinical sign accompanying a comorbid primary neurological or other medical condition. Virtually all pathophysiologic processes can produce myoclonus as a sign, including inflammation, infectious diseases, paraneoplastic syndromes, structural lesions, adverse effects of substances (licit and illicit), metabolic derangement, and degenerative disorders. Seizure(s) may be a nontrivial component of the underlying primary illness, but the seizure is not the primary myoclonus phenotype in secondary myoclonus. In secondary myoclonus, more than a single neurological system is usually affected. Sleep, cognitive, and movement impairments are commonly co-occurring.

Drug-induced

• Multiple drug classes and multiple different agents within each class can cause myoclonus, making it imperative that the entirety of a presenting patient's armamentarium be probed for potential causation.
• Renal or hepatic dysfunction can raise the levels of myoclonus-inducing drugs and their metabolites in the bloodstream.
• Drug-induced myoclonus is frequently reversible upon withdrawal of the causative agent. However, a layer of complexity also obtains here: in some cases, discontinuation (notably of anticonvulsants or sedative-hypnotics) can precipitate myoclonus.
• Polypharmacy that includes multiple potentially offending drug classes (or multiple agents from a single class) can produce synergistic interactions, thus increasing the likelihood of emergent myoclonus. 
• Bismuth
• Bismuth has been used as a wound dressing in maxillofacial and neurosurgical interventions and aftercare for burns and skin grafts. In these settings, bismuth can cause a toxic metabolic encephalopathy that includes myoclonus, along with ataxia, altered mental status, and seizures. 
• Acute toxicity often precipitates renal failure; subacute or chronic exposure can cause the bismuth encephalopathy syndrome. Diagnosis is via blood and urine bismuth levels, which correlate well with each other but are unable to differentiate between acute and chronic toxicity. 
• Bismuth toxicity can occur with both oral and topical formulations. 
• Bismuth toxicity can be easily missed or overlooked, necessitating a high index of suspicion. 
• Untreated, bismuth encephalopathy can progress to coma and death.[8]
• Lithium
• Lithium is frequently prescribed to individuals with mood disorders such as bipolar disorder, acute mania, or hypomania; a coarse tremor is a well-known side effect of the medication. 
• Lithium toxicity can cause focal motor seizures and generalized convulsions; with mild toxicity—or even at therapeutic levels—electroencephalographic slowing may be seen. Using sophisticated EEG techniques,[9] recent work has suggested that lithium-induced myoclonus is likely cortical, arising largely from the cerebellum.[10]
• Other drug classes and agents prominently associated with myoclonic adverse effects (noninclusive):  
  • Antibiotics: penicillins, cephalosporins, carbapenems, fluoroquinolones
  • Narcotics: tramadol, hydromorphone, morphine, and fentanyl
  • Anesthetics: lidocaine, midazolam, propofol
  • Anticonvulsants: gabapentin, pregabalin, lamotrigine, phenobarbital, phenytoin, valproic acid, vigabatrin, primidone, and carbamazepine
  • Psychiatric medications: neuroleptics, antidepressants (tricyclics and selective serotonin reuptake inhibitors)
  • Anti-Parkinsonian drugs (L-dopa, bromocriptine, amantadine, selegiline)
  • Cardiac medications: amiodarone[11] and calcium channel blockers
  • Chemotherapeutic agents: cyclophosphamide, ifosfamide, busulphan, chlorambucil, and etomidate[12]    

Metabolic conditions causing myoclonus

• Metabolic derangement, arising from organ failure or electrolyte abnormalities (or both, in unhappy scenarios), can produce myoclonus, which can be subtle, multifocal, or even persistent, as in myoclonic status epilepticus. 
• Prognosis in metabolic myoclonus depends on the severity of the underlying derangement and on whether eventual reversibility proves possible.
• Asterixis[13] is a type of so-called negative myoclonus, less a jerk than a brief lapse in postural tone (usually with the arms extended and wrists dorsiflexed), giving the appearance of “flapping” due to a momentary loss of muscle tone in agonist muscles, followed immediately by a compensatory jerk of the antagonistic muscles. Once primarily associated with hepatic dysfunction (the "liver flap"), asterixis has subsequently also been noted in myriad other conditions, including Guillen-Barre syndrome,[13] cephalosporin toxicity,[39] and hypermagnesemia,[14] among others.
• Common precipitants of metabolic myoclonus include:                                                                                                  
• Renal failure
• Post-dialysis syndrome
• Hepatic failure
• Disorders of glucose metabolism (hypo- or hyper-)
• Deficiency of biotin (including in multiple carboxylase deficiency) or vitamin E
• Hyperthyroidism
• Hyponatremia
• Metabolic alkalosis
• Hypoxia

Neurodegenerative

Myoclonus is a frequent sign in neurodegenerative diseases of many sorts, although only rarely does it aid in parsing the differential diagnosis of the underlying neurodegenerative disorder.

• Spinocerebellar degeneration 
  • Dyssynergia cerebellaris myoclonica (aka Ramsey Hunt syndrome). This form of progressive myoclonic ataxia is similar to PME, albeit here, the ataxia is the dominant phenotype, rather than the frequent seizures that are seen in PME.
  • Other forms of spinocerebellar degeneration, including myoclonus as one aspect of the phenotype, include:
    • Friedreich’s ataxia, a hereditary multisystem disorder for which a transcription factor was given FDA approval in early 2023;[15]
    • Ataxia-telangiectasia, a rare autosomal recessive disorder in which chorea or dystonia occur more commonly than myoclonus;[16]
    • Spinocerebellar ataxia describes a group of related genetic diseases (with an autosomal dominant inheritance pattern) that cause progressive impairments in cognition, motor control, and coordination, all amid considerable phenotypic heterogeneity.[17] 
• Basal ganglia degeneration: Various degenerative disorders of the basal ganglia feature myoclonus in their phenotypes. A partial list of these disorders includes: 
  • Wilson disease,
  • torsion dystonia,
  • neurodegeneration with brain iron accumulation (previously known as Hallervorden–Spatz syndrome),
  • progressive supranuclear palsy (PSP),
  • Huntington disease,
  • Parkinson disease (PD),
  • multiple system atrophy (MSA),
  • corticobasal degeneration (CBD), and
  • dentatorubropallidoluysian atrophy.[1]
  • At one point in time, PSP and CBD were grouped under a rubric of “atypical parkinsonism” or “Parkinson-plus syndromes,” but both are now recognized as tauopathies.[18]  PD and MSA are synucleinopathies.
• Parkinson disease (PD) 
  • Myoclonus occurs much less commonly in idiopathic PD than the more pathognomonic and easily recognized high-amplitude, low-frequency, and usually asymmetric rest tremor. That said, rest tremors seem to occur less frequently in those PD patients who have concomitant myoclonus. In PD patients with myoclonus, the cortical burden of aberrant α-synuclein is markedly higher than in those who do not exhibit myoclonus.
  • In the mid-1970s, myoclonus in Parkinson disease was understood as an adverse effect of therapy with levodopa.[19] Bromocriptine and amantadine have also been associated with myoclonus as an adverse effect, although pharmacological databases (eg, Epocrates) no longer list this effect. Myoclonus is recognized more as an “off” phenomenon in PD according to current understanding.
  • Orthostatic myoclonus of the lower extremities can exacerbate unsteadiness in PD.[20]
• Corticobasal degeneration (CBD)
  • CBD refers to a broad spectrum of disorders described by fronto-basal-ganglia degeneration, leading to a progressive decline in movement, coordination, cognition, and swallowing.
  • Asymmetric rigidity is a hallmark of CBD, where it occurs in combination with dystonia, myoclonus, apraxia, cortical sensory deficits, or (sometimes, and certainly most famously) an alien limb phenomenon.
  • Both action- and stimulus-sensitive myoclonus can occur in CBD, where the myoclonus can be either asymmetric or focal. A myoclonus-predominant phenotype has been reported.[21]
  • A recent CBD autopsy case series reported that myoclonus occurred in slightly more than a quarter of the cases, which is relatively lower than previously reported prevalence rates.[22] 
• Progressive supranuclear palsy (PSP)
  • Motoric deficits in PSP can occur anywhere along the neuraxis. Several discrete phenotypes have been described,[23] centering on bradykinesia, rigidity, gait freezing and falls, supranuclear ocular motor impairment, dysphagia, dysarthria, incontinence, an array of behavioral changes, including frontal cognitive dysfunction, and sleep disorders.[24]
  • Myoclonus is uncommon in the classical PSP phenotype, known as Richardson’s syndrome, in which symmetrical axial rigidity is accompanied by vertical gaze palsy, severe akinesia, and falls.
  • Myoclonus does occur in the combined PSP-CBS phenotype, which features prominent asymmetric dystonia, cortical sensory deficits, and the alien limb phenomena.[25] 
• Major neurocognitive disorders (dementias)
  • Major neurocognitive disorders easily number more than 50, but the “Big 4” are Alzheimer disease (AD), vascular dementia, dementia with Lewy bodies (DLB), and the frontotemporal lobar degeneration (FTLD). A recent single-institution retrospective analysis of myoclonus in neurodegenerative disease conducted at a renowned dementia research center reported a cumulative probability of developing myoclonus of 42.1%; the probability was highest in DLB (58.1%), and in all groups, the relative frequency of myoclonus increased with earlier age-at-onset.[26]
  • Most commonly, myoclonus in dementia has a cortical generator, although this is not universal. In late-onset myoclonic epilepsy in Down syndrome, for example, an EEG correlate is often missing in the later stages of the disease, indicating the presence of a subcortical, or more distal, generator.
  • In DLB, the myoclonic jerks usually have a large amplitude and are more likely to occur at rest than in PD, where the myoclonus can easily be confused with resting tremor. Myoclonus occurs in nearly 60% of older adults with DLB.[26]
  • In AD, myoclonus occurs in nearly half of patients, where it is usually distal, multifocal, and low in amplitude. In younger individuals, early-onset Alzheimer disease can be phenotypically similar to the progressive myoclonic epilepsies. Lamotrigine can lower the seizure threshold in patients with AD, so other medications should be used, preferably for the treatment of the myoclonus.[27]
  • Rapidly-progressive dementias, like Creutzfeld-Jakob Disease (CJD), have near-pathognomic myoclonus, insofar as myoclonus becomes essentially 100% prevalent over the disease course; at onset, the myoclonus is most commonly distal and multifocal but over time often becomes more diffuse and generalized. Nonetheless, the spectrum of movement abnormalities in CJD is unusually vast, ranging from akinesia through hypokinetic to hyperkinetic phenomenologies; in one series, myoclonus appeared in approximately 70%, second only to ataxia, which appeared in 90%.[28]

Inflammatory/paraneoplastic/infectious causes of myoclonus

• Inflammatory: steroid-responsive encephalopathy associated with autoimmune thyroiditis
  • Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT; or, more familiarly, Hashimoto encephalopathy) can present with a spectrum of neurological dysfunction. Diagnosis is via elevations in antibodies to thyroglobulin and thyroid peroxidase.[29] 
  • Myoclonus is often part of the clinical presentation, along with tremor, ataxia, seizures, and psychosis. One recent systematic review noted that the myoclonus is usually stimulus-sensitive and lacks EEG correlation; it was present in 42% to 65% of reported cases.[30]
  • “Pretreatment” criteria include (1) subacute onset of cognitive impairment, psychiatric symptoms, or seizures; (2) euthyroid status or mild hypothyroidism; (3) serum thyroid peroxidase antibodies (TPOAb) >200 IU/mL; (4) absent neuronal antibodies in serum/CSF; and (5) no other etiologies. However, a recent analysis determined that the pretreatment criteria are poor predictors of eventual steroid responsiveness, with the result that the authors recommended systematic exclusion of antibody-mediated encephalitis before steroid initiation.[31]. 
  • Other presentations are also possible, including pure cerebellar ataxia; case reports in the medical literature have also described presentations entirely without encephalopathy.
• Inflammatory: Other Autoimmune Encephalitides (AIE)
  • Some epidemiological studies suggest that AIE may occur as commonly as infectious encephalitis, with an AIE estimated prevalence rate of 13.7/100 000.[32] Other studies contend that AIE is a rare disorder with a cumulative incidence of approximately 3 to 9 per million person-years.[33]
  • In recent years, an ever-growing number of antibodies targeting either neuronal surface or synaptic antigens has been identified and characterized, including N-Methyl D-Aspartate Receptor (NMDAR)-antibody and Leucine-rich glioma inactivated (LGI1)-antibody.[32]
  • Atypical presentations of neurodegenerative decline should always prompt consideration of possible underlying autoimmune etiologies. Relevant symptoms favoring AIE over more typical neurodegenerative diseases might include 1) subacute rather than gradual deterioration; 2) a waxing and waning pattern; 3) any history of autoimmune disease; 4) concurrent epileptic seizures; and 4) presence of myoclonus.
  • In AIE, movement disorders, including myoclonus, have been associated with multiple antibodies, including anti-NMDAR, CASPR2, LGI1, Ri, Hu, or CV2/CRMP5.[34][35][34]
  • Autoimmune encephalitis (AIE) may present with prominent cognitive disturbances without overt inflammatory changes in MRI and CSF. Identifying these dementia mimickers is crucial because patients with AIE generally respond to immunotherapy.[36] However, when an AIE is misdiagnosed, the resulting anti-inflammatory treatment also has associated morbidity - systemic steroids can cause infection, psychosis, avascular necrosis of the hip, and heart failure; intravenous immunoglobulin can cause aseptic meningitis, confusion, and hair loss; other immunosuppressive medications (eg, rituximab, azathioprine, and others) often cause headache and nausea.
• Paraneoplastic Syndromes (PNS)
  • Paraneoplastic disorders arise when a misguided immune-mediated pathogenetic process occurs remotely to the underlying primary malignancy.[37]
  • In adults, paraneoplastic phenomena are associated with an array of underlying cancers, including lung, breast, ovarian, and renal tumors.
  • Though recent population-based studies of the incidence of PNS are few, PNS appears to be a rare disorder, with incidence varying between 1.6 to 8.9 per million person-years. A reasonable interpretation of this data suggests that underdiagnosis or misdiagnosis is occurring, likely along with underreporting.[38]
  • Stiff Person Syndrome (SPS) describes an array of conditions characterized by fluctuating muscle stiffness, superimposed spasms, and exaggerated startle.[39]
  • Progressive encephalomyelitis with rigidity and myoclonus (PERM) is one (of several) SPS subtypes. In PERM, rigidity and myoclonus occur in approximately 80% of diagnosed cases, often with an attendant increase in falls, which can be disabling. Numerous antibodies have been associated with PERM, including glycine receptor antibodies, which can be nonneoplastic.[40] [37]
  • Opsoclonus-myoclonus Syndrome (OMS)[41] [42]
    • OMS is colloquially known as “dancing eyes, dancing feet syndrome,” and in humans, it has been associated with a spectrum of malignancies, including breast, lung, ovarian, and testicular cancers.
    • Opsoclonus, from Greek for eye (“ops”) and violent, confusing movements (“klonus”), is defined as rapid, irregular, and nonrhythmic eye movements that are nonetheless conjugate. Linear and rotational movements occur in combination and are rapid, with frequencies up to 10 movements per second.
    • OMS in adults can also emerge due to infectious (eg, Covid),[43][44] tick-borne illnesses[45]), autoimmune, or drug-induced etiologies.[3]
    • In comparison with idiopathic OMS, paraneoplastic OMS has a more refractory course.[39]
    • Many antibodies have been associated with OMS, prominently including ANNA2 (anti-Ri), ANNA1 (anti-Hu), Ma2, CRMP5 (anti-CV2), NMDA-R, and GluD2.[39]
• Infections: The list is multitudinous and noninclusive.
  • Subacute sclerosing panencephalitis (post-viral; measles)
  • Arbovirus encephalitis
  • Herpes simplex encephalitis
  • Human T-lymphotropic virus
  • Human immunodeficiency virus
  • Coronavirus infection[44][46]
  • Progressive multifocal leukoencephalopathy (JC virus)
  • Bacterial infection including these causative organisms: Streptococcus, Clostridium, Treponema pallidum (syphilis), Cryptococcus, Borrellia burgdorferei (Lyme disease), and Tropheryma whipplei (Whipple disease) 

Posthypoxic Myoclonus

The clinical spectrum of post-hypoxic movement disorders incorporates post-hypoxic dystonia, ballism, choreoathetosis, akinetic-rigid syndrome, and myoclonus among its diverse manifestations.[47]

More specifically, causes of post-hypoxic myoclonus include cardiac arrest, respiratory obstruction, anesthesia accident, carbon monoxide poisoning, hemorrhagic shock, hanging, and drowning.[48]

Posthypoxic myoclonus (PHM) presents with focal or generalized, stimulus-sensitive myoclonic jerks beginning days to weeks after cardiac arrest, sometimes without reliable correlates on electroencephalography (EEG).[5]

According to the timing of emergent myoclonus, PHM can be acute or chronic.[49] Acute PHM usually emerges within the first 48 hours after an ischemic hypoxic brain injury; it can be multifocal or generalized, and it often appears while the patient is still comatose. Many cases have a subcortical generator, but cortical myoclonus also occurs; the latter increases the risk for the development of myoclonic status epilepticus. EEG findings in acute PHM range from burst suppression, spike-wave activity, diffuse slow background, and generalized periodic discharges, to alpha coma. Prognosis in acute PHM is likewise variable, ranging from complete recovery to death.

Chronic PHM, also known as Lance-Adams syndrome (LAS), has a generally more favorable prognosis, owing at least in part to the usual absence of an underlying ischemic brain injury. LAS usually emerges on a subacute or chronic time scale, but emergence as early as the first 96 hours has been reported, which can lead to diagnostic uncertainty between PHM and LAS. EEG findings in LAS may feature spike-wave, poly-spike activity, or slow frequency waves; up to 50% of EEGs in LAS demonstrate focal epileptiform activity at the vertex, considered by some to be a defining feature of LAS.[49]

Because it is effective for both cortical and subcortical origins of myoclonus, clonazepam is, in many cases, the first-line therapy for both PHM and LAS. Other agents, generally either antiseizure medications or anesthetic agents, are also often used; treatment with more than one medication is frequently necessary, and refractoriness may nonetheless remain.

Functional Jerks

A psychogenic etiology can give rise to phenomena difficult to distinguish from the "organic" etiologies of myoclonus. Hints that a so-called functional etiology is at play include acute onset, sudden spontaneous resolution, amelioration with distraction, and inconsistencies in amplitude, frequency, and distribution of the jerks.[50] In some cases, identification of a Bereitschaft potential ("preparing" potential) or event-related desynchronization on EEG, indicators of premotor activity in advance of a voluntary movement, can support the diagnosis of functional jerks. However, these phenomena can be technically challenging to observe, so their absence should not be used to eliminate the possibility of a functional etiology.[51]

Epidemiology

Regrettably, our most current knowledge of the epidemiology of myoclonus is grievously outdated. As of 1990, the lifetime prevalence of myoclonus was 8.6% in the overall population.[3] It is generally accepted that myoclonus is an important contributor to many syndromes and diseases, but its incidence and prevalence are almost certainly underestimated because myoclonus is most often secondary to another cause or underlying disorder. In some diseases that feature myoclonus as a phenotypic component, prevalence and incidence estimates vary quite widely,[52][53] underscoring the crucial lack of disorder-specific epidemiology: it is worthy of further study.[54] It should be recognized that a single disease or patient may have more than a single myoclonus neurophysiology type. One study found that electrophysiological testing in the context of clinical findings altered the myoclonus diagnosis and the subtype in 53% of patients.[55] 

Pathophysiology

Myoclonus can arise anywhere along the neuraxis, from the cerebral cortex to the peripheral nerves. Researchers theorize that myoclonus may emerge due to motor strip hyperexcitability, abnormalities or deficiencies in neurotransmitter receptors, imbalances among neurotransmitters, or underlying network abnormalities that have yet to be elucidated. 

One of the chief classification schemes for the evaluation of myoclonus rests upon identifying the neuroanatomic generator of the myoclonus. Myoclonus can arise from loci in the cortex, cortico-subcortical regions (eg, brain stem), subcortical non-segmental overlap, segmental (brain stem or spinal cord), and the peripheral nerves.

Cortical Myoclonus 

Cortical myoclonus may occur spontaneously, in response to somatic stimuli, or during movement. Cortical myoclonus describes those muscle jerks that can be traced back to hyperexcitability in the cerebral cortex, usually in the motor strip in the precentral gyrus, conceptually described by the motor homunculus.[56] Cortical myoclonus predominantly affects body regions with the most extensive cortical homuncular representations, such as the hands and face. Current understanding posits that cortical myoclonus results from spreading cortical hyperexcitability: excitation begins in one spot on the homunculus, then spreads with a multifocal distribution, and culminates in jerking movements of the limbs with synchronous (sometimes bilateral) activation of adjacent muscles. 

EMG discharges in cortical myoclonus are usually less than 100 ms long; spread to adjacent and antagonistic muscles can be observed.[3] Examples of cortical myoclonus include chronic post-hypoxic myoclonus (LAS), the progressive myoclonic epilepsies, neurodegeneration of the Alzheimer or Lewy body type, and some drug-induced (eg, lithium) reactions.  

Cortical-Subcortical Myoclonus

Cortical-subcortical myoclonus usually occurs in the setting of primary generalized epilepsy. Abnormal and excessive neuronal activity spreads between cortical and subcortical networks, creating diffuse electrical excitation distinct from localized cortical myoclonus, and necessitating a wholly separate neurophysiological classification. Typically, generalized myoclonus occurs due to the widespread and simultaneous spread of excitation over the sensorimotor cortex.[3] 

EMG discharges in cortical-subcortical myoclonus are characteristically brief, averaging between 50 to 100 ms. The discharges visible on surface EMG can be correlated temporally to a spike- or polyspike EEG waveform.

Examples include the myoclonic seizures in JME and myoclonus associated with absence seizures.

Subcortical-Nonsegmental Myoclonus

Physiological mechanisms and results of electrophysiological testing are more heterogeneous in subcortical-nonsegmental myoclonus than in either cortical or cortical-subcortical myoclonus. Myoclonus can be generated at any of multiple subcortical locations, when the excitation is transmitted to descending motor pathways. 

EMG discharges in subcortical-nonsegmental myoclonus tend to be longer in duration than in cortical or cortical-subcortical myoclonus, often as long as 200 ms. Muscle activation patterns are also variable, including bidirectional rostral-caudal distribution, a purely caudal distribution, or multifocal distribution. As a general rule, the EEG in subcortical-nonsegmental myoclonus does not show a correlation to the muscle jerks; indeed, in most cases, the EEG is normal. However, given that multiple physiological and technical factors may influence electrophysiological recordings, subcortical-nonsegmental should never be diagnosed solely on the absence of findings typical of cortical myoclonus.[1]

In brainstem reticular myoclonus, an initial discharge arises in muscles (trapezius and sternocleidomastoid) innervated by the spinal accessory nerve (CN XI); this is followed by the rostral spread of the excitation, which causes jerks first in the muscles of facial expression (CN VII) and then masseter jerks (CN V). In propriospinal myoclonus, the generator arises in the cervical or thoracic spinal cord and is again followed by muscle recruitment in both rostral and caudal directions; this kind of myoclonus sometimes arises from spinal lesions, but it can also be seen in sleep transitions (physiological myoclonus). In myoclonus dystonia, the discharge pattern is multifocal; the cause is thought to be genetic mechanisms affecting the basal ganglia and cerebellothalamic circuits. This myoclonus syndrome reportedly is exquisitely responsive to ethanol.

Segmental Myoclonus

Segmental myoclonus refers to myoclonus arising in and limited to 1-3 contiguous segments of the brainstem or spinal cord. Discharges are often persistent and are not usually impacted by the level of consciousness, motor activity, stimuli, or other exogenous factors. 

EMG discharges in segmental myoclonus are distinctive by their duration, which can be as long as 500 ms, and their highly rhythmic nature.[3] As with subcortical-nonsegmental myoclonus, no EEG correlate of muscle activity is usually observed in segmental myoclonus. 

The classic example of segmental myoclonus is palatal myoclonus, which can occur idiopathically or due to dentato-rubro-olivary (the Guillain Mollaret triangle) lesions. Occasionally, the palatal myoclonus may be functional. 

Spinal segmental myoclonus can arise from vascular, neoplastic, inflammatory, infectious, and idiopathic causes. Anterior horn cell hyperexcitability in the affected segment is felt to be the cause due to loss of spinal neuron inhibition. Segmental myoclonus is often refractory to pharmacological intervention. 

Peripheral Myoclonus

Peripheral myoclonus arises from one or more elements of the peripheral nerve itself (eg, root or nerve). Multiple muscles within a single nerve distribution may be affected. Direct motor nerve irritation (usually due to compression) or peripheral nerve lesions altering central nervous system motor pathways have been advanced as proposed mechanisms. 

Hemifacial spasm, wherein the generator lies in the muscles of facial expression innervated by the facial nerve (CN VII), is the best-known example of peripheral myoclonus. 

History and Physical

Myoclonus can be an overwhelming and intimidating presentation for the practitioner who does not have an efficient and practical approach to carrying out the clinical evaluation.

History

A comprehensive history is the critical foundational starting point in evaluating myoclonus, with a particular focus on aspects of the history that could be relevant to the emergence of myoclonus. Both the history and the physical examination can provide salient clues to aid in distinguishing symptomatic from the other subtypes of myoclonus.

Key elements of the history crucial to review in every patient with myoclonus include:

• Age at onset: childhood, early adulthood, or late adulthood.
• Phenomenology of the myoclonus: Triggers (eg, auditory stimulus, movement, and tactile, visual, or emotional stimuli), body parts involved, and whether the myoclonus displays rhythmicity.[57]
• Family history: A positive family history hints at the possibility of a genetic contribution to the myoclonus, including possibly from the myoclonic epilepsies.
• Chronicity
  • acute, suggesting perhaps a toxic effect of medication;
  • subacute, suggesting possible infectious (or postinfectious), inflammatory, paraneoplastic, or toxic-metabolic causation;
  • or chronic, which is usually indicative of genetic or neurodegenerative causes. Of note, the chronic onset of focal myoclonus may herald underlying neoplasm.
• Progression: rapidly progressive, slowly progressive, static.
• Coinciding factors
  • new medication(s), newly-discontinued medications, or dosage changes in continuing medications,
  • sick exposures,
  • the presence of concomitant symptoms, especially if they are neurologic (eg, cognitive decline, paresthesias, weakness, “spells” of altered awareness, or loss of consciousness), or
  • whether consumption of alcohol ameliorates the myoclonic jerks (think myoclonus-dystonia).

Physical and Neurological Examination

The examination facilitates the acquisition of important information about 1) the body distribution of the myoclonus, 2) its constancy, and 3) whether the myoclonus can be induced by stimulus (eg, auditory, tactile, startle). Every examination should assess for movement characterization of the myoclonus and include a thorough neurological examination. 

The clinician must evaluate the distribution of the movements, including amplitude, and observe for any activation characteristics. Neuroanatomical correlation is not perfect, but can guide the clinician's initial thinking along the following lines:

• Myoclonus in the resting state suggests a spinal or brainstem source, but action-induced myoclonus points to a cortical origin.
• Focal and multifocal jerks, prompted by voluntary action, typify cortical myoclonus.
• Spinal segmental myoclonus is usually also focal, although contrary to cortical myoclonus, it is not action-induced and is occasionally stimulus-sensitive.
• Generalized myoclonus is usually subcortical (brainstem or propriospinal myoclonus); a cortical generator will occasionally be revealed for generalized myoclonus. 

To elicit eloquent neurologic signs, a comprehensive neurological examination is paramount in the evaluation of myoclonus:

• Cognitive dysfunction may indicate underlying dementia (or dementia prodrome).
• Signs of parkinsonism may point to an underlying tau- or synucleinopathy.
• Dystonia may corroborate suspicions of myoclonus-dystonia.
• Cerebellar signs may point to a cerebellar ataxia syndrome.[58] 
• Eye movements should be assessed to rule out (or in) opsoclonus-myoclonus.
• Finally, a careful examination should be conducted to assess for signs of systemic disease.  

Evaluation

As with the history and physical examination, it is vital to have a systematic approach to ancillary testing in the workup of myoclonus. Ancillary testing builds on the history and physical examination to identify the underlying etiology. The first goal is always to determine whether a reversible cause for the myoclonus exists. The fundamental building blocks of a systematic approach include basic laboratory testing, ancillary laboratory testing when warranted, and more comprehensive testing if needed and based on the results of the initial stages of testing. Following Occam's Razor,[59] should the myoclonus present along with non-myoclonus signs and symptoms, the clinician must seek a unifying single diagnosis.

Basic Laboratory Testing

Tests for serum electrolytes, glucose, renal and hepatic function tests, and at least basic thyroid studies (ie, thyroid stimulating hormone and circulating free T4 thyroid hormone) should be obtained in nearly every patient who presents with myoclonus. No laboratory work is necessary in clear-cut cases of physiologic myoclonus, where there are no signs or aspects of the history raising concerns for other etiologies. 

Drug and toxin screening is essential to consider in the case of acute onset myoclonus or the hospital (inpatient or emergency department) setting. 

A lumbar puncture is essential whenever possible infectious or inflammatory causation is suspected. Standard studies for cell counts, glucose, and protein should always be obtained; antibody and paraneoplastic panels should be sent in the setting of possible inflammatory or paraneoplastic causes of myoclonus. Concern for possible CJD necessitates sending CSF for RT-QUIC testing[60] to the National Prion Disease Pathology Surveillance Center in Cleveland, OH. 

Neurophysiological Testing and Structural Neuroimaging Neurophysiological Testing

Electroencephalography (EEG) must be performed in all but the most straightforward presentations of physiological myoclonus. EEG alone can advance the diagnostic reasoning in cases of myoclonic epilepsies. However, the most broadly informative approach combines EEG with electromyography (EMG) on muscles of interest. The technique of EEG-EMG back-averaging (correlation of electrical activity on EEG in the brain with muscle jerking on EMG) shows cortical discharge preceding the activity on electromyography. Even when the EEG has no clinical correlate, the absence of myoclonic cortical activity can be instructive, as in cases of subcortical-nonsegmental myoclonus (eg, propriospinal, brainstem reticular myoclonus, or myoclonus-dystonia). Evoked potentials can be helpful in some segmental or peripheral myoclonus cases, but they are not pathognomic. 

Structural Neuroimaging

Brain MRI should be considered and is particularly important in cases of symptomatic myoclonus. Brain MRI can aid in discovering ischemic insult, mass lesion, or infectious nidus. The study should be ordered with gadolinium if inflammation, infection, or mass lesion figure prominently in the differential diagnosis. Brain MRI can also be helpful in segmental myoclonus cases; segmental or peripheral myoclonus necessitate imaging of the spinal cord and even peripheral nerves in some cases. 

More Comprehensive Testing

If the etiology of the myoclonus remains unclear after the initial rounds of testing, more comprehensive testing will be needed. The issue is that the corpus of eligible tests is enormous, underscoring the demand for a targeted strategy with a stepwise evolution.[3] Possible avenues to pursue include genetic testing, which could be either for specific genetic markers or for possibly whole exome sequencing,[58] inflammatory and paraneoplastic antibodies (if not previously obtained), or specific toxins not previously evaluated. A lumbar puncture may be helpful if not performed during earlier testing. 

Treatment / Management

Myoclonus is notoriously refractory to pharmacotherapy. Additional complexity arises due to the relatively undeveloped evidence base and near total absence of formal, consensus- and evidence-based guidelines.[3] For these reasons, it is a near-maxim that the etiology of the myoclonus, as it emerges from a proper history and neurophysiological assessment, must drive the treatment choice.[1] In many cases, polypharmacy will become necessary to control the myoclonus. Cumulatively, these factors preclude the creation of precise treatment algorithms and greatly complicate the approach to treatment in myoclonus.

Should the myoclonus etiology remain opaque, empirical treatment should be explored. In all cases, the selected treatment must be measured against its possible adverse effects. This is particularly the case given that some treatments have the potential to worsen cognitive function, cause neuropsychiatric comorbidities, or impair movement coordination. 

In most cases, standard titration schedules for a given medication are adequate when used to treat myoclonus. However, for patients already burdened by polypharmacy in the setting of multiple and complex medical problems, slower titration schedules should always be considered. Metabolic insufficiency—especially renal or hepatic compromise—should prompt the use of lower doses and slower titration schedules. 

In some cases of myoclonus, disability occurs even after optimal symptomatic treatment has occurred. Physical and occupational therapy warrant examination for inclusion in the overall treatment paradigm, especially for symptomatic myoclonus.

In physiological myoclonus, pharmacotherapy is usually not necessary. In cases of suspected drug-induced myoclonus, a trial off of the offending causal agent (or dose reduction, in some cases) along with correction of any associated metabolic derangement is the necessary first step. 

Treatment of Cortical Myoclonus

Cortical hyperexcitability is an intrinsic cause of cortical myoclonus, and, consistent with this, anti-epileptic drugs (AEDs) are the usual first-line treatment approach. That said, AEDs can, in some cases, worsen the myoclonus.[61] Valproic acid, levetiracetam, clonazepam, and perampanel are commonly used, with at minimum some case reports as the underlying evidence base (although not all agree fully) for each agent. Topiramate and zonisamide are used on occasion in the setting of 

Levetiracetam

A relatively "clean" AED, with renal rather than hepatic clearance and a comparatively mild side effect profile, levetiracetam[62] is frequently the first-line therapy in cortical myoclonus. Its antimyoclonic effect is theorized to arise from its binding to the synaptic vesicle protein 2A (SV2A), although the precise mechanism of action has not yet been established. Standard dosing regimens fall between 1000 and 3000 mg daily, divided into two doses. Side effects include headache, dizziness, and fatigue. Behavioral side effects sometimes limit its usage, but these are more common in the treatment of epilepsy(3-4%) than myoclonus.[62]

Valproic acid 

An older AED valproic acid (VPA) can be beneficial in cortical myoclonus, albeit considered a second-line approach by some well-known authorities[3] and a first-line treatment for myoclonic epilepsies by others.[1] VPA likely acts through multiple mechanisms that increase the availability of gamma-aminobutyric acid (GABA) through amplified synthesis and decreased degradation.[62] Standard dosing regimens range between 500 and 2000 mg daily, with higher doses often needed to achieve symptomatic control. VPA is regarded as a relatively "messy" AED, given its manifold adverse effects. These include hepatotoxicity, metabolic derangement (SIADH, hyponatremia), blood dyscrasias (pancytopenia, thrombocytopenia, myelosuppression, aplastic anemia, and others), encephalopathy, psychosis, and suicidality number only some of the serious adverse events associated with VPA. Common side effects include headache, gastrointestinal distress, weight gain, tremor, sleep issues (both somnolence and insomnia can occur), and alopecia. VPA is contraindicated in pregnancy (and in women who wish to become pregnant). 

Clonazepam

A benzodiazepine, clonazepam, likely facilitates GABAergic transmission. A scant array of (now outdated) case reports suggest a possible role in posthypoxic and neurodegenerative etiologies of myoclonus. Benefits have also been described for clonazepam in the settings of opsoclonus-myoclonus, spinal myoclonus, and especially in cases of chronic posthypoxic myoclonus. 

Perampanel

A relative newcomer among AEDs, perampanel gained FDA approval in 2012. Though its exact mechanism is unknown, it is believed to antagonize α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), thus reducing glutamate-mediated neuronal excitation. As with other AEDs used in myoclonus, the evidence base for perampanel in myoclonus is thin, consisting primarily of small (eg, n of 2)[63] cases series suggesting its utility in cortical myoclonus arising in the myoclonic epilepsies[64] and in posthypoxic myoclonus.[65][66] Behavioral adverse effects include a range of dysfunction: worsening depression, hostility, aggression, suicidal and homicidal ideation, and abuse. Common side effects include gastrointestinal discomfort, vertigo, headache, fatigue, and weight gain, among many others.[65](A1)

Treatment of Cortical-Subcortical Myoclonus

Though there is some overlap with the treatment of cortical myoclonus, some authorities believe cortical-subcortical myoclonus demonstrates a "distinct profile of therapeutic efficacy."[1] VPA remains the usual first-line approach to the syndromes of generalized epilepsy featuring myoclonus (primarily JME and absence syndromes). Currently, clinical equipoise characterizes the use of lamotrigine in JME, particularly in comparison to VPA; rarely does lamotrigine reportedly worsen myoclonus in JME. 

Treatment of Subcortical-Nonegmental Myoclonus

Given the etiologic heterogeneity that attends this myoclonus category, so is there heterogeneity in treatment approaches. Clonazepam is reasonable to try first in cases ranging from reticular reflex myoclonus to myoclonus-dystonia (which often responds exquisitely to alcohol, too) to propriospinal myoclonus. Zonisamide, an inhibitor of carbonic anhydrase that blocks sodium and calcium channels, demonstrated benefit in myoclonus-dystonia in a recent(ish) double-blind crossover trial in a small cohort (n = 23) of patients.[67](A1)

Levetiracetam and VPA typically have limited utility in subcortical-nonsegmental myoclonus. (goes under Treatment of Subcortical-Nonegmental Myoclonus

Treatment of Segmental Myoclonus

Segmental myoclonus is infamously unresponsive to pharmacotherapy. Clonazepam and baclofen are often tried empirically. OnabotulinumtoxinA (Botox) injections have shown promise in a small set of now outdated publications[1] concerning palatal myoclonus and spinal myoclonus; close monitoring for serious adverse events is essential with Botox, as these can include dysphagia, respiratory compromise, and dysautonomia. 

Treatment of Peripheral Myoclonus

At one time, carbamazepine, usually used to treat complex partial seizures, was the mainstay of treatment in the most common example of peripheral myoclonus, hemifacial spasm. Today, Botox is the preferred approach, with surgical intervention as a consideration in cases where a compressive lesion is found.

Treatment of Functional Jerks

It is crucial to achieve the maximal possible certainty of the functional diagnosis before attempting to treat psychogenic movement disorders of any sort, and this includes functional jerks. The first step in treatment must always be to explain the functional nature of the symptoms in an empathic manner that eschews any suggestion that the problem is "all in the head." Treatment usually requires a multidisciplinary approach, individualized to the patient. Pharmacotherapy of the functional jerks is not indicated in the vast majority of cases, but comorbid psychiatric conditions should, in all cases, be addressed with medications in the presence of positive indications. Other modalities that may help in functional jerks include cognitive behavioral therapy, physical therapy, physical activity, and biofeedback. 

Treatment Trends

Deep brain stimulation (DBS) involves the implantation of an electrical stimulator — akin to a cardiac pacemaker — to send electrical signals to structures responsible for body movement. Oddly, implantation sites are subcortical; positive case reports in the literature of DBS' benefits in cortical myoclonus (such as posthypoxic myoclonus[68] and the progressive myoclonic epilepsies) suggest that additional research into site selection and etiology-based efficacy is now warranted, even for cortical myoclonus.[3] To date, the best evidence base, including long-term follow-up,[69] exists for the use of DBS to treat myoclonus-dystonia syndromes,[70][71][72] although larger-scale studies are still needed to validate and replicate the more preliminary results.[1](B3)

Transcranial Magnetic Stimulation (TMS), a form of neuromodulation, offers insights into neuronal plasticity in the sensorimotor cortex in particular and cortical excitability more generally, although studies in large cohorts remain aspirational.[73] TMS also holds out tantalizing prospects as a nonpharmacological and noninvasive treatment approach, but further study is needed to investigate efficacy, especially over the long term.[1]

Precision Medicine

Though still in its infancy as a therapeutic approach to myoclonus, precision therapies are targets of mounting interest for pharmacotherapy. In neuroinflammatory disorders, for example, "designer" monoclonal antibodies that target chemo- and cytokines along with soluble receptor ligands and proteomic small molecule therapies represent recent advances with exciting potential for targeted therapies.[74] (B3)

Differential Diagnosis

The differential diagnosis for myoclonus is exceptionally broad. In considering a patient presenting with myoclonus, the clinician's goal must be to distinguish myoclonus from other paroxysmal and abnormal movements. The list of such abnormal movements is long, but at a minimum, consideration should be given to tremor, tics, dystonia, chorea, hemiballismus, and seizures. 

• Tremor: Tremor is, by definition, a rhythmic and oscillating movement. With some uncommon exceptions, myoclonus is not rhythmic, making differentiation from myoclonus relatively simple. 
• Tics: Tics are short, abnormal, and stereotyped movements that may occur in a stereotyped sequence. Commonly observed motoric tics include grimacing, grunting, coughing, sniffing, repetitive blinking, or vocalizations. Simple tics can be challenging to distinguish from myoclonus, but the compelling urge to move experienced with tics is mainly absent from myoclonus. 
• Dystonia: Dystonia is an abnormal movement characterized by bizarre posturing of the limbs or twisting and repetitive movements; in both cases, the dystonic movements arise from sustained muscle contractions. 
• Chorea: Chorea is a movement disorder causing sudden, unintended, and uncontrollable smooth or jerky movements of the arms, legs, and facial muscles. As such, it can be challenging to distinguish from myoclonus. Generally, choreiform movements will be more sustained and less lightening-like than myoclonus. 
• Hemiballismus: Hemiballistic movements are coarser, often more violent, and almost always larger in amplitude than myoclonus: the unilateral "flinging" movement of the arm or leg in hemiballismus ("ballism" means 'to throw") is much more dramatic than in myoclonic "jerks." The etiology of hemiballismus is classically that of a vascular insult (stroke) to the contralateral subthalamic nucleus. In recent years, however, the anatomic localization has been expanded to include that of the globus pallidus interna (part of the basal ganglia), and the pathologic diagnosis has broadened to include non-ketotic hyperglycemia and HIV infection.[75]  
• Seizure activity: several epilepsy syndromes, both well-known and rare, include myoclonic jerks. In many instances, the myoclonus is the seizure ictus; in others, it is considered a seizure "fragment." Examples of the latter include eyelid myoclonus occurring as part of an absence seizure or myoclonus associated with focal motor seizures (eg, epilepsia partialis continua). 
• Functional jerks: Since functional myoclonus is among the most common functional movement disorders, it is crucial to differentiate it from organic myoclonus. This can be done through the localization of the movements. Features favoring an organic cause over a functional one include consistent phenomenology, insidious onset, or response to benzodiazepines or antiepileptic medication.[76] The presence of spontaneous periods of remission, pronounced reduction of the myoclonus with distraction, acute onset, and sudden resolution favors the functional diagnosis of myoclonus.[77]

Finally, myoclonus can be a feature of myriad neurological diseases and disorders. Perhaps most pathognomonically associated with "startle myoclonus" in Creutzfeld-Jakob disease, myoclonus can also be a feature of neurodegenerative diseases like Alzheimer disease, dementia with Lewy bodies, Parkinson disease, frontotemporal dementia, and disorders of basal ganglia or spinocerebellar degeneration, among others. Inflammatory conditions—infectious, post-infectious, antibody-mediated, or paraneoplastic—often feature myoclonic jerks. Metabolic derangement, toxidromes, physical encephalopathy, focal neurological insults, trauma, and malabsorption all can, but do not invariably, cause myoclonus.  

Prognosis

Myoclonus can cause serious disability. Despite the availability of a diverse array of pharmacological and other interventions that are at least partially effective, the treatment of myoclonus remains challenging. Treatment with medication is variably effective, and the emergence of drug-related adverse events often impedes it. Evidenced-based guidelines for pharmacologic therapy are mostly lacking, as are results from large randomized clinical trials.  

Complications

Myoclonus can be the cause of significant disability, and impairments can include problems with gait, activities of daily living, and possibly the emergence of intolerable frustration, which can, in turn, prompt depressive symptoms. As noted, myoclonus is often treatment-refractory, in some cases even to polypharmaceutic approaches, and this naturally exacerbates the frustrating nature of living with myoclonus. Occupational therapy can assist with the use of assistive devices to help manage myoclonic movements with large excursions. Similarly, physical therapy can help instruct the correct and safe way to employ ambulatory assistive devices.