Abstract

Introduction

Myoclonus can be the cause of significant disability. Whether it is present at rest, with muscle activation, or from stimuli, myoclonic jerks interfere with performing or initiating the desired correct movement for a given task [1]. As a result, impairment in activities of daily living and intolerable frustration occur. Classically defined, myoclonus is a sudden, brief, lightening-like muscle jerk arising abnormally from the nervous system [2]. Any movement, of short or long-duration, that arises intrinsically from the muscle, such as fasciculation, spasm, or cramp, is not considered myoclonus. There is no strict rule for what duration constitutes the brevity threshold for myoclonus. However, the definition emphasizes how quickly the movement reaches its highest amplitude and then descends back to its original posture. Thus, myoclonic movements are the most sudden and brief muscle jerks that can be produced from involuntary nervous system stimulation. Non-myoclonic jerks occur in dyskinesias such as chorea, ballismus, tardive dyskinesias, and dystonia.

Myoclonus occurs via many different etiologies and basic pathophysiological mechanisms [1]. Classification by both etiology and physiology is necessary to optimize the treatment strategy. Etiological classification is best performed by using a modified version of the scheme proposed by Marsden et al. [2]. A modified version is shown in Table 1. This classification system uses four main categories: physiologic, essential, epileptic, symptomatic. Each of these categories has certain characteristics and clinical presentations. Physiologic myoclonus occurs normally in people, but the degree to which it occurs varies between individuals. Both the clinical history and examination suggest normal circumstances. Myoclonus can occur as a normal phenomenon of sleep. “Hypnic jerks” occur as generalized jerks when falling asleep and represent one example of physiologic myoclonus. The normal startle jerk is another example. Essential myoclonus is mostly monosymptomatic, relatively non-progressive, and is usually associated with minor disability. A modern view of essential myoclonus acknowledges hereditary and sporadic forms, as well as other associated signs and symptoms [3]. Most notably, the hereditary myoclonus–dystonia syndrome is the best defined essential myoclonus entity. Epileptic myoclonus occurs in the setting of a chronic seizure disorder in which myoclonus is a major seizure phenotype. The myoclonic seizures in juvenile myoclonic epilepsy are a prime example of epileptic myoclonus. Symptomatic myoclonus, the largest category, consists of a variety of disparate etiologies [4]. All symptomatic myoclonus cases are secondary to a defined disorder, either neurologic or medical. Symptomatic examples of myoclonus are commonly associated with other neurological signs and symptoms, such as dementia, delirium, and other movement disorders. The placement of a specific myoclonus case into one of these four categories is the first recommended step towards diagnosis.

Table 1

Etiology myoclonus classification scheme. Modified from Marsden et al. [2]

I. Physiologic myoclonus (healthy individuals)

A. Sleep jerks (e.g., hypnic jerks)

B. Anxiety-induced

C. Exercise-induced

D. Hiccough (singultus)

E. Benign infantile myoclonus with feeding

II. Essential myoclonus (primary symptom, non-progressive history)

A. Hereditary (autosomal dominant)

a. Myoclonus–dystonia syndrome (including ε-sarcoglycan mutations)

b. Other

B. Sporadic

III. Epileptic myoclonus (seizures dominate, part of chronic seizure disorder)

A. Fragments of epilepsy

a. Isolated epileptic myoclonic jerks

b. Focal motor seizures (includes epilepsia partialis continua)

c. Idiopathic stimulus-sensitive myoclonus

d. Photosensitive myoclonus

e. Myoclonic absences in petit mal epilepsy

B. Childhood myoclonic epilepsy

a. Infantile spasms

b. Myoclonic astatic epilepsy (Lennox–Gastaut)

c. Cryptogenic myoclonus epilepsy (Aicardi)

d. Awakening myoclonus epilepsy of Janz (juvenile myoclonic epilepsy)

C. Progressive myoclonus epilepsy: Baltic myoclonus (Unverricht–Lundborg)

IV. Symptomatic myoclonus (secondary, progressive, or static encephalopathy dominates)

A. Storage disease

a. Lafora body disease

b. GM2 gangliosidosis (late infantile, juvenile)

c. Tay-Sachs disease

d. Gaucher disease (noninfantile neuronopathic form)

e. Krabbe leukodystrophy

f. Ceroid-lipofuscinosis (Batten)

g. Sialidosis (cherry-red spot) (types 1 and 2)

B. Spinocerebellar degenerations

a. Ramsay Hunt syndrome

b. Friedreich ataxia

c. Ataxia-telangiectasia

d. Other spinocerebellar degenerations

C. Basal ganglia degenerations

a. Wilson disease

b. Torsion dystonia

c. Hallervorden-Spatz disease

d. Progressive supranuclear palsy

e. Huntington disease

f. Parkinson disease

g. Multisystem atrophy

h. Corticobasal degeneration

i. Dentatorubropallidoluysian atrophy

A. Dementias

a. Creutzfeldt–Jakob disease

b. Alzheimer’s disease

c. Dementia with Lewy bodies

d. Frontotemporal dementia (including mutations of Tau and others)

e. Rett syndrome

B. Infectious or postinfectious

a. Subacute sclerosing panencephalitis

b. Encephalitis lethargica

c. Arbovirus encephalitis

d. Herpes simplex encephalitis

e. Human T-lymphotropic virus I

f. HIV

g. Postinfectious encephalitis

h. Miscellaneous bacteria (Streptococcus, Clostridium, other)

i. Malaria

j. Syphilis

k. Cryptococcus

l. Lyme disease

m. Progressive multifocal leukoencephalopathy

A. Metabolic

a. Hyperthyroidism

b. Hepatic failure

c. Renal failure

d. Dialysis syndrome

e. Hyponatremia

f. Hypoglycemia

g. Nonketotic hyperglycemia

h. Multiple carboxylase deficiency

i. Biotin deficiency

j. Mitochondrial dysfunction

k. Hypoxia

l. Metabolic alkalosis

m. Vitamin E deficiency

B. Toxic and drug-induced syndromes (modified from [1])

a. Toxins

i. Bismuth

ii. Heavy metals

iii. Methyl bromide

iv. Dichlorodiphenyltrichloroethane

v. Organic compounds

b. Psychiatric medications [e.g., cyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, lithium, tardive syndrome (anti-psychotic use)]

c. Anti-infectious agents

d. Opiates

e. Anti-seizure agents

f. Anesthetics

g. Contrast media

h. Cardiac medications (e.g., calcium channel blockers, anti-arrhythmics)

i. Drug withdrawal

j. Other medications

B. Physical encephalopathies

a. Posthypoxia (Lance-Adams)

b. Post-traumatic

c. Heat stroke

d. Electric shock

e. Decompression injury

C. Focal nervous system damage

a. Vascular (ischemic, hematoma, etc.)

b. Post-thalamotomy

c. Tumor

d. Trauma

e. Inflammation (e.g., multiple sclerosis)

f. Developmental (e.g., “dysplasia”)

g. Peripheral nervous system

D. Malabsorption

a. Celiac disease

b. Whipple disease

E. Eosinophilia–myalgia syndrome

F. Inflammatory and paraneoplastic encephalopathies

a. Opsoclonus–myoclonus syndrome

i. Idiopathic

ii. Paraneoplastic [ANNA-1 (anti-Hu), ANNA-2 (anti-Ri), absent antibodies]

iii. Infectious

iv. Other

b. Voltage-gated potassium channel antibody syndromes

c. N-methyl-D-aspartate receptor antibody encephalitis

d. Thyroperoxidase antibody syndromes

e. Ophelia syndrome

G. Exaggerated startle syndrome

a. Hereditary

b. Sporadic

H. Hashimoto encephalopathy

I. Multiple system degeneration

a. Allgrove syndrome

b. DiGeorge syndrome

c. Membranous lipodystrophy

J. Unknown or “idiopathic” (familial or sporadic)

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At this time, there is little evidence-based data available for myoclonus treatment. Two sources have discussed levels of evidence for myoclonus treatment in various instances [5, 6]. Both of these sources designate the lower class or grade of evidence for most examples of treatment indication. For most myoclonus types, results of multiple placebo-controlled double-blind studies are not available. Many articles on the treatment of myoclonus are case reports or small series. This article will focus on current practical treatment strategies. It has been established that delineation of myoclonus physiology is critical for the formulation of specific and successful myoclonus treatment strategy [1, 6]. From the standpoint of the individual myoclonus patient, a treatment strategy is synthesized from etiology classification, physiology classification, best available evidence, and the patient-specific clinical characteristics of the myoclonus that create disability.

Pathophysiology and Neurophysiological Classification of Myoclonus

The pathophysiology of myoclonus, as well as its modern physiologic classification, refers to not only the site(s) of the abnormal neuronal circuits believed to create the myoclonus, but is also combined with the physiologic mechanism that generates and/or propagates the excitation. Currently, we do not know the exact neuronal circuits that are abnormal in any example of myoclonus. However, clinical neurophysiology testing is the best tool for gathering evidence to formulate physiological classification of myoclonus [7, 8]. This testing commonly uses electroencephalography (EEG), surface electromyography (EMG), EEG–EMG polygraphy with back-averaging, evoked potentials (most commonly somatosensory evoked potentials), and EMG responses to stimulation. Other techniques include coherence analysis and transcranial magnetic stimulation. Results from the test battery are used to classify the myoclonus according to a physiological classification for myoclonus. Here, the defining characteristics for each physiological classification are discussed. In the section on treatment, other physiological aspects will be given as they directly relate to treatment mechanism (s) under the categories. Categories of this classification scheme are:

• cortical;

• cortical–subcortical;

• subcortical–nonsegmental;

• segmental;

• peripheral.

Cortical Myoclonus

The cerebral cortex is the most common origin for myoclonus. The jerks are most often multifocal, but focal, segmental, and generalized myoclonus may also occur. Action myoclonus, i.e., myoclonus exacerbated/triggered by muscle activation, is common. As functional ability depends on precise muscle activation, overall treatment benefit often depends on the reduction of action myoclonus. An example of cortical myoclonus surface EMG polygraphy is given in Fig. 1. In Fig. 1, multiple multifocal short-duration hypersynchronous myoclonus EMG discharges may be appreciated with co-contraction of agonists and antagonists, and across muscle segments. To satisfy criteria for cortical myoclonus, there must be a focal time-locked cortical transient demonstrated that precedes the myoclonus by a short latency (<40 ms for arm). Although this may be observed on gross EEG–EMG polygraphy, back-averaging is a more sensitive and reliable method to derive EEG transients time-locked to myoclonus from ongoing EEG activity. EEG back-averaging of the myoclonus EMG discharges from Fig. 1 is shown in Fig. 2. Such EEG transients typically have a focal distribution with a biphasic or triphasic spike waveform beginning with a positive deflection that precedes the onset of the myoclonic discharge by 6–22 ms in the upper extremity: the more distal muscle the myoclonus is recorded from, the longer the time interval [7]. The duration of the transient is 15–40 ms. Compared with the spike amplitude seen on the EEG in partial epilepsy, amplitude of the spike that is time-locked to the myoclonus is small, often 5–20 μV. The conduction of the spike to motor neuron pools is presumed to occur by fast-conducting corticospinal (pyramidal) pathways. The maximum of the transient is usually located over the sensorimotor cortex at the central or centro-parietal electrode according to anatomical somatotopic mapping, contralateral to the myoclonus. Enlarged cortical SEP waves and enhanced long latency EMG responses to electrical nerve stimulation are not uniformly present, but support a cortical origin for myoclonus. Elevated cortico-muscular coherence of the myoclonus EMG discharge that localizes to the contralateral sensorimotor cortex supports a cortical origin for myoclonus. Examples of cortical myoclonus occur post-hypoxia (“Lance-Adams syndrome”), lipid storage disorders, dementia syndromes, Parkinson’s disease, and certain drug-induced etiologies such as lithium treatment.

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Fig. 1

Surface electromyography polygraphy recording from multiple left arm muscles in a patient with cortical myoclonus during muscle activation. Note the hypersynchronous and multifocal nature of the discharges that commonly occur with co-contraction of agonists and antagonists, sometimes across muscle segments. The electroencephalography back-averaging of these discharges is shown in Fig. 2

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Fig. 2

Electroencephalography (EEG) back-averaging of the surface electromyography discharges that are shown in Fig. 1. The EEG transient has a right centro-parietal maximum, consistent with left arm cortical myoclonus. The EEG transient begins 24 ms before the 0 ms trigger point, consistent with corticospinal transmission of the myoclonus generation. The x-axis is 200 ms across left to right full extent. The y-axis is 100 μV bottom to top full extent

Basic Treatment Strategy for Myoclonus

The treatment of myoclonus is often challenging. Myoclonus occurs in so many different forms and disorders such that a simple and straightforward recipe for treatment does not exist. Multiple treatments have been tried for myoclonus, but results are often inconsistent. Disabling side effects are common. Polypharmacy is common in myoclonus treatment, but it has many pitfalls. Because of these many challenges, it is necessary to have a treatment strategy that derives from the best diagnosis and physiological information that is available. Figure 3 shows a treatment algorithm for myoclonus. It begins with clinical history and examination, and appropriate testing. Depending on the evaluation results, treatment is tailored to the circumstance and physiological classification. All treatments outlined in Fig. 3 should be considered “off-label” and based on few, if any, controlled treatment trials. As such, clinical judgment must be exercised. Details and explanation are given below.

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Fig. 3

Myoclonus treatment algorithm. See text for approach and details

The diagnosis of myoclonus may be fairly certain because of the medical circumstances, genetic test results, etc. However, the determination of the diagnosis responsible for the myoclonus is not always clear and may require extensive investigation. If the etiology is unclear, then a rigorous diagnostic evaluation should be planned [1]. First, the clinical presentation category of the etiology classification scheme should be determined to be either physiologic (normal), essential (sporadic or hereditary), epileptic, or symptomatic. Second, basic testing is undertaken with easily available methods. These include central nervous systemic imaging, blood and urine testing for toxic metabolic causes, and antibody testing for inflammatory and para-neoplastic disorders. However, the absence of para-neoplastic antibodies should not be assumed to rule out neoplastic presence. Third, clinical neurophysiology testing with EEG and surface EMG should be performed. If a cortical source is possible, SEPs, EMG responses to stimulation, and referral to a laboratory that performs EEG–EMG polygraphy with back-averaging is recommended. Finally, depending on the clinical scenario and results so far available, advanced testing with a variety of established and emerging methods may be warranted. These may include, but are not limited to, tissue diagnosis, genetic testing, cerebrospinal fluid examination, enzyme and other biochemical testing, other imaging, and malabsorption testing.

The first consideration should be given to reversing the underlying etiology of the myoclonus. The most straightforward example is that of drug-induced myoclonus, and discontinuation of the drug usually eliminates the myoclonus. Lithium and antidepressant medication are two examples [20]. Other potentially reversible causes of myoclonus are an acquired abnormal metabolic state, removable toxin, or an excisable lesion. Some cases of propriospinal myoclonus have a lesion affecting the spinal cord that correlates with the origin from which the myoclonus EMG discharges spread. In such instances, it is possible for the propriospinal myoclonus to be partially or totally relieved by lesion removal [21]. Paraneoplastic myoclonus has also been known to improve, on occasion, if the cancer is treated effectively. Before treating any etiology, the risks need to be considered for the patient. Nevertheless, owing to the limitations of symptomatic therapy, the treatment of the underlying etiology may be the best option if the clinical circumstances are appropriate.

For the majority of myoclonus cases, treatment of the underlying disorder is usually not possible or effective, and symptomatic treatment is justified if the myoclonus is disabling enough. Before making the decision to treat on a symptomatic basis, the clinician needs to consider whether potential side effects outweigh potential benefit. One example is a patient with significant dementia and myoclonus. Although the myoclonus may be suppressed with therapy, sedation and increased cognitive difficulty may well not be worth the decreased myoclonus. Another example is the generalized myoclonus that can occur immediately after prolonged hypotension due to cardiac arrest. This myoclonus is difficult to treat in a nonaggressive manner. It may be suppressed by anesthesia or paralytic agents temporarily, but there is risk in doing this. In some circumstances of myoclonus treatment, multiple drug combinations may be necessary for symptomatic treatment but also may increase side effects. Amelioration of the myoclonus is rare for symptomatic treatment. However, important improvement may be attained with decreased disability.

If the risks are judged to be warranted clinically, the best strategy for symptomatic treatment is derived from using physiological classification. A drug treatment used for one physiological classification may not work well in another or may even induce worsening. For example, a medication that can work in some instances of segmental myoclonus may not work in cortical myoclonus. If the myoclonus physiology classification cannot be determined, then presuming the myoclonus physiology that usually occurs in that particular diagnosis is a reasonable way to cautiously proceed. If both the diagnosis and myoclonus physiology are unknown, there is little to guide an approach to treatment. In this instance, the clinician should be prepared for possible poor results until the reason for the myoclonus is defined. The myoclonus treatment strategy given below is organized by the physiological classification of the myoclonus.

Cortical Myoclonus Treatment

Suppression of myoclonus may come from lowering the excitatory drive and/or increasing inhibition of the responsible neurons that drive the excitatory output. Two observations suggest cortical myoclonus arises from abnormal excitation of corticospinal output: 1) cortical myoclonus shows a time-locked pre-myoclonus EEG discharge reflecting apical dendrite excitation of pyramidal neurons; 2) myoclonus event latency is consistent with pyramidal tract conduction. Common occurrence of multifocal activation is allowed by hyperexcitability across the relatively large sensorimotor cortex homunculi. Such hyperexcitability may be exacerbated by voluntary or reflex activation. Within this region, large pyramidal neurons of layers III and V are presumed to be subject to the cortical hyperexcitability that causes excessive and brief myoclonus discharges down their axons [22]. Decreasing the excitatory drive of these neurons and their circuits may come from altering ionic conductance or decreasing excitatory neurotransmission, such as via the neurotransmitter glutamate system. Chandelier, basket, and other gamma-aminobutyric acid (GABA)-ergic neurons are powerful sources of inhibition for pyramidal cortical neurons and associated circuits. Enhanced inhibitory activity through these neurons and/or their GABA-ergic receptors has a potential therapeutic effect for cortical myoclonus. For treatment of cortical myoclonus to be effective, it must affect these intrinsic circuits within the sensorimotor cortex.

Cortical–Subcortical Myoclonus Treatment

The myoclonus in primary generalized epilepsies falls under this physiological classification, including myoclonic seizures. In primary generalized epilepsies, the abnormally activated circuit is comprised of neocortical pyramidal neurons, thalamic relay neurons, and the GABAergic neurons of the nucleus reticularis thalami [39]. This network is widely distributed; when synchronized burst-firing occurs within it, generalized epileptic seizures can manifest. Myoclonus may occur if such burst-firing affects motor cortex. Treatment of cortical–subcortical myoclonus must decrease the reverberating excitatory activity of these cortical–subcortical circuits. GABA_A and GABA_B activation, as well as Na⁺ and Ca²⁺ conductance, are mechanisms that are believed to play a crucial role in burst-firing [40]. Mutations of proteins associated with GABA receptors and ionic conductance are known to produce myoclonic seizures and other generalized epilepsies [41]. Treatments that intercede in these mechanisms have potential for a therapeutic action for cortical–subcortical myoclonus.

Valproic acid is the major drug of choice for cortical–subcortical myoclonus overall [42]. However, the controlled evidence for efficacy is mostly for juvenile myoclonic epilepsy [43, 44]. Less impressive results are seen in other childhood myoclonic epilepsy syndromes [45]. Why is valproic acid seemingly more effective for cortical–subcortical myoclonus than levetiracetam, while the relative efficacy is reversed for cortical myoclonus? Both agents do have treatment efficacy for both physiological types of myoclonus. However, as aberrant ionic conductance (e.g., Na⁺ and Ca²⁺) plays a substantial role in cortical–subcortical myoclonus pathophysiology, the ability of valproic acid to affect ionic conductance may be more significant than for levetiracetam [46]. The precise reason is not known. Lamotrigine may be used alone or as an adjunct to valproic acid [46]. The role for ethosuximide, zonisamide, and clonazepam are mainly as adjuncts [42]. Polypharmacy may be useful, but is limited by side effects. Paradoxically, anti-seizure medications sometimes increase seizures or myoclonus in these syndromes, including phenytoin, carbamazepine, and lamotrigine [47–49]. Intravenous valproic acid or levetiracetam can be useful in myoclonic seizure status [50]. Apart from the myoclonus per se, the treatment of both primary and secondary generalized myoclonic epilepsy syndromes has extensive algorithms organized around age of onset and subtypes [51–53].

Subcortical–Nonsegmental Myoclonus Treatment

The mechanisms of subcortical–nonsegmental myoclonus are heterogeneous. Moreover, the aberrant circuitry for these myoclonus examples is even less understood than it is for cortical myoclonus. The therapeutics of this myoclonus physiology overlaps that of cortical myoclonus, but also has important differences. Although GABAergic mechanisms can be leveraged in these myoclonus disorders, cholinergic and monoamine systems also seem to offer an opportunity for therapeutics. Standard anti-seizure treatments, such as valproic acid and levetiracetam, are not as consistently useful in subcortical–nonsegmental myoclonus when compared with their use in cortical or cortical–subcortical myoclonus.

Segmental Myoclonus Treatment

Segmental myoclonus is generated at a circumscribed level along the brainstem and/or spinal neuraxis. Often, it is produced by a local lesion causes a focal neuronal circuit disruption with motor neurons having an abnormal bursting discharge pattern [17]. This lesion may occur in the gray matter of the spinal cord or in the central region of the brainstem reticular formation while preserving motorneuron output. A disconnection of afferent white matter tracts that project to nuclei or gray matter that, in turn, project to motor neurons can also generate the bursting discharge pattern of segmental myoclonus. At a segmental level, important inhibitory circuits are GABAergic and/or glycinergic, and these are potential mechanisms on which to base symptomatic treatment. Descending monoaminergic pathways also seem to play a role in modulating motor activity. These neurotransmitter systems provide a possible basis to suppress the segmental myoclonus bursting pattern. A variety of lesions may cause segmental myoclonus but vascular, tumor, trauma, infectious, and idiopathic and/or “essential” diagnoses account for most cases.

Peripheral Myoclonus Treatment

The myoclonic movements of hemifacial spasm will often respond to botulinum toxin therapy along with the more tonic or sustained contractions [77]. Surgery to remove pressure on the seventh cranial nerve may be warranted in certain situations. Other causes of peripheral myoclonus may also respond to botulinum toxin injections, and this may also improve any associated discomfort with the movements [78]. Carbamazepine may be tried as drug therapy for peripheral myoclonus, but a satisfactory response is uncommon.

Treatment of Psychogenic Jerks

Psychogenic or “functional” jerks are diagnosed when the movements are thought to be a symptom of psychiatric disease [79]. The term “psychogenic jerk” is preferred to “psychogenic myoclonus” because the movements are usually not typical for myoclonus and often are longer or more complex. Psychogenic jerks offer diagnostic and treatment challenges. For example, it has been pointed out that psychogenic jerks are commonly misdiagnosed as propriospinal myoclonus [64]. The diagnostic approach to psychogenic jerks may include neurophysiologic studies, but these are not always possible or definitive, so diagnosis strongly rests on the psychiatric aspects of the patient and the atypical nature of the movements. Treatment should begin with explaining to the patient the nature of the disorder. When in the context of non-malingering, the patient should be told that the jerks are not their fault and that successful treatment is possible. A psychiatrist should consider treatment of any psychiatric disease that is present, such as anxiety and/or depression. Both physical therapy-based and cognitive behavioral therapies have been reported to be useful [80]. The clinician should keep in mind that each of these cases tends to be unique, so individualized diagnosis and treatment options are common.

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