Myoclonus is defined as sudden, brief, shocklike movements caused by muscle contractions (positive myoclonus) or inhibitions (negative myoclonus). It can be confusing to clinicians because of its varied clinical appearance and disparate etiologies. Patients will usually call their myoclonus “jerks,” “jolts,” “shakes,” or “spasms.” Myoclonic movements are now recognized as having many possible etiologies, anatomical sources, and pathophysiologic features, including an association with epilepsy.1 However, this relationship with epilepsy has not always been clear. This chapter discusses that relationship and distinguishes the two disorders based on differences in phenotype, physiology, and treatment.
The term myoclonus was first described by Nikolaus Friedreich in 1881.2 He was confident that myoclonus should be distinguished from epilepsy.3 However, the 20th century saw increased study of both entities, and the two became intertwined. Because both myoclonus and epileptic seizures are manifested by paroxysmal, fast motor phenomena, the potential for overlap is obvious. Indeed, despite the close relationship between myoclonus and epilepsy, it has become evident that real distinctions between them are justified on the basis of phenotype, physiology, and treatment.
In Olmsted County, Minnesota, the average annual incidence rate for myoclonus as of 1976–1990 was 1.3 cases per 100, 000 person-years.4 The lifetime prevalence of myoclonus was 8.6 cases per 100,000 population. Symptomatic myoclonus (72%) was the most common clinical category, followed by epileptic myoclonus (17%) and essential myoclonus (11%).4 Posthypoxic state, neurodegenerative disease, and epilepsy syndromes are the most common causes of myoclonus. Toxic-metabolic and drug-induced cases are particularly common in the hospital setting.
Myoclonus may be classified by examination findings, physiology based on clinical neurophysiology testing, and clinical presentation/etiology.
The myoclonus examination findings are classified by distribution, temporal profile, and activation characteristics of the myoclonic movement. The distribution can be focal, multifocal, segmental, or generalized. A multifocal myoclonus distribution is widespread, noncontiguous, and irregular, but there may be bilaterally synchronous movements as well. A generalized myoclonic jerk refers to a simultaneous muscle contraction that is both diffuse and bilateral. The temporal profile of myoclonic jerking can be continuous or intermittent, as well as rhythmic or irregular. If intermittent, the myoclonus can occur as isolated or repetitive jerks. The activation of the myoclonus may be at rest (spontaneous), induced by various stimuli (reflex myoclonus), or induced by voluntary movement (action myoclonus), or some combination of these. All the above activation characteristics should be noted as absent or present.
Understanding the neurophysiological aspects of myoclonus is of critical importance. The term neurophysiology used here implies both the neuroanatomical source of the myoclonus and the activity within the motor circuits generating the jerk. Certain patterns can correlate with diagnostic classification as well as predict which treatments may work more effectively. Both exam characteristics and clinical neurophysiology testing are used to determine the physiological classification of the myoclonus in a particular patient. Common techniques used in this testing include electroencephalography (EEG), surface electromyography (EMG)-EEG polygraphy with back-averaging, evoked potentials, long latency EMG responses, and coherence analysis. Details on how these methods are applied to myoclonus investigation are provided in other reviews.5,6 Major categories of the physiological classification refer to the neuroanatomical source of the myoclonus. Under each category, subtypes are defined by certain results of the test battery, as well as examination findings.6 The categories with some explanation are given below.
A focal cortical discharge from the sensorimotor cortex occurs and is followed by myoclonus after an interval due to corticospinal transmission. Myoclonus may occur with reflex sensory stimulation (cortical reflex myoclonus), with muscle activation (cortical action myoclonus), or from rest (e.g., focal motor seizure), or any combination of the above. EMG discharge duration is typically <75 msec, and discharges often occur in trains (Figure 16-1). A focal back-averaged EEG transient is present. Enlarged cortical somatosensory evoked potential (SEP) and enhance long-latency EMG responses are characteristic of cortical reflex myoclonus physiology.5 The myoclonus usually occurs in a widespread multifocal muscle distribution. Secondary generalization of the focal (or multifocal) cortical discharge may give rise to widespread and bilaterally synchronous myoclonus.
This physiology represents abnormal paroxysmal and widespread excessive oscillation in bidirectional connections between cortical and subcortical sites. It produces myoclonus in primary generalized epileptic syndromes (e.g., juvenile myoclonic epilepsy [JME]) and in other instances (e.g., “minipolymyoclonus”). Frontal cortical areas and the thalamus are the primary cortical and subcortical involved areas. There is usually generalized or at least widespread muscle involvement with emphasis in the upper body and proximal/axial distribution. The EMG discharge duration is typically <100 msec, but the discharges may become longer if they begin to fuse with more tonic movements as the seizure evolves. The associated EEG transient (e.g., spike and wave) is usually diffuse and correlates with the EMG discharges. Various myoclonic epilepsy syndromes have typical discharge frequencies, such as 2 to 3 Hz, 3 Hz, or 3 to 6 Hz. However, multiple discharge frequencies in a single patient or syndrome may be seen.
Myoclonus is generated from subcortical or suprasegmental sources (e.g., myoclonus-dystonia syndrome). In some instances, both rostral and caudal spread from the generator site occurs (e.g., reticular reflex myoclonus, propriospinal myoclonus). There are heterogeneous patterns seen within this classification. EMG discharge duration may range from <100 msec to a few hundred milliseconds. In addition, there may be variation of discharge duration within individual patients. Even though the excitation may be generated within a specific segment of the neuraxis, the spread of muscle activation occurs far beyond the local segment. No EEG changes precede the myoclonus. Cortical SEPs are normal, and long-latency EMG responses are unremarkable.
Myoclonus is generated at a particular segment or contiguous segments of the brainstem and/or spinal cord. The myoclonus manifests at or close to that particular segment or contiguous segments of the body (e.g., palatal myoclonus, spinal segmental myoclonus). EMG discharge duration is typically >100 msec. There are usually rhythmic EMG discharges that are fairly persistent and resistant to stimuli.
Myoclonus can be generated from a peripheral site (e.g., hemifacial spasm). Variable EMG discharge duration and irregularity are characteristic within and between patients.
The major clinical classification scheme used for myoclonus has four major categories. They are physiological, essential, epileptic, and symptomatic (secondary). Each major category has certain clinical presentation characteristics under which specific etiologies and syndromes are listed.7 Under each category, the neurophysiology will vary among the specific entities listed under that major category. Thus, the information from clinical classification and the neurophysiology are complementary. The diagnostic evaluation of myoclonus begins with a thorough history and physical exam, as well as determination of the clinical classification category. If needed, basic, neurophysiology, and special testing usually provides an opportunity to determine a diagnosis of the underlying etiology of the myoclonus.8
This myoclonus occurs in normal individuals.7 There is minimal or no associated disability, and the physical exam reveals no relevant abnormality. Jerks during sleep or sleep transitions, such as “massive myoclonic jerks” (hypnic jerks) and “partial myoclonic jerks,” are the most familiar examples of physiological myoclonus.9 Another observer, such as a sleep partner, commonly detects the physiological jerk occurrence.
These disorders manifest pathologic myoclonus but are relatively unassociated with other clinical features, including seizures.
In this context, epileptic myoclonus is used in a broad sense to mean myoclonus associated with a chronic seizure disorder (i.e., epilepsy). Seizures dominate the clinical picture in epileptic myoclonus. The myoclonus is usually paroxysmal and spontaneous, although there may be stimulus sensitivity or provoking factors. The underlying etiologies may be idiopathic, genetic, or a static encephalopathy. The most common phenotype for epileptic myoclonus is the myoclonic seizure, followed by the partial motor seizure syndromes. By convention, a myoclonic seizure is a myoclonic jerk or multiple jerks caused by a classic seizure discharge on EEG. Myoclonic seizures and their disorders will be covered in more detail below.
One example of a partial seizure phenotype is epilepsia partialis continua. In this instance of epileptic myoclonus, the jerks are spontaneous and focal, occur irregularly or regularly at intervals no longer than 10 sec and are confined to one part of the body, and continue for a period of hours, days, or weeks.10
This category has the most etiologies, and the myoclonus results secondary to an identifiable disorder, whether neurologic or medical. However, a chronic seizure disorder is not the only prominent manifestation of this type of myoclonus. Etiologies and syndromes of pathologic myoclonus are discussed below.
Myoclonic seizures are epileptic seizures in which the characteristic movement manifestation is myoclonus, and the myoclonus has a much greater tendency to be generalized than in partial motor seizures. They may be confused with other seizures that result in jerks (e.g., atonic and tonic seizures). “True” myoclonic seizures result in brief positive myoclonus.11 The myoclonus is accompanied by a generalized (primary or secondary) ictal epileptiform EEG discharge; although the myoclonus itself is usually generalized, it can be segmental or occasionally focal. Myoclonic epilepsy syndromes commonly manifest other seizure types besides myoclonic seizures. Myoclonic seizures occurring in a primary generalized epileptic syndrome exhibit a cortical-subcortical myoclonus physiology, whereas those occurring in a secondary generalized epileptic syndrome exhibit a focal cortical physiology with a tendency to spread rapidly.
JME is the best known and most common of the myoclonic epilepsy syndromes. It is classified among the idiopathic generalized epilepsies in accordance with the classification system of the International League Against Epilepsy.12 Its incidence is 0.5 to 6.3/100,000 per year, and the vast majority of patients present between the ages of 12 and 18.13 Although JME may present clinically with myoclonic jerks or a generalized tonic-clinic seizure, the history always reveals jerking on an ongoing basis. Myoclonic seizures in the early morning are typical. Dropping or throwing items due to the jerks is common. During the myoclonic seizure, consciousness may be difficult to evaluate but is usually preserved. Although generalized tonic-clonic seizures occur in almost all cases, absence seizures occur in ∼20%.14 Exacerbating factors include sleep deprivation, alcohol consumption, photic stimulation, and menstruation.
EEG is useful in making the diagnosis, although abnormalities are not seen in all untreated cases.15 The typical findings are trains of generalized spikes, polyspikes, and 4 to 6 Hz irregular spike-wave complexes. Fragments of these discharges, as well as asymmetry, may occur during the recording. The discharges may or may not accompany the myoclonic jerks. Photosensitivity of these discharges is common, but once the photosensitivity is demonstrated, the stimulation should be turned off so as to not trigger a generalized tonic-clonic seizure.
A positive family history is common in JME (40%).12 Even in those families with a known mutation, the phenotypes vary. Multiple mutations have been associated with JME, and the mutations most commonly have been found in ion channel or neurotransmitter receptor genes.16,17 It is likely that these genetic influences occur via neuronal excitability. This is an attractive idea, as increased widespread excitability in both cortical and subcortical networks has been implicated in JME. Such physiology is consistent with a cortical-subcortical myoclonus physiology classification. Imaging studies have found abnormalities in both the frontal cortex and the thalamus in JME.18 Because there is so much clinical and complex genetic heterogeneity in JME, there are undoubtedly multiple basic etiologies for this syndrome.
The treatment of JME consists of avoiding exacerbating factors and medical therapy. Good sleep and sunglasses if needed for photosensitivity should be considered. Valproic acid is a common therapy for JME, and 20 to 30 mg/kg/day is a standard dose. Some of the newer antiepileptic medications are being used with increasing frequency, however, because of valproic acid’s adverse effects and occasional ineffectiveness. These medications include levetiracetam, topiramate, lamotrigine, zonisamide, and clonazepam. Myoclonic seizures, as well as the other seizure types, are responsive in the vast majority of cases.19 All of these drugs have multiple possible side effects and circumstances that may affect the appropriateness of their use.19,20 In particular, lamotrigine exacerbates some patients’ myoclonus when treating JME. Carbamazepine, phenytoin, gabapentin, tiagabine, and vigabatrin have been associated with worsening of seizures in JME and should be avoided.20
There are a few distinct syndromes in which myoclonus can be associated with absence seizures. In simple absence seizures, such as childhood absence epilepsy, there may be myoclonus of the eyelid, other facial muscles, and neck.21 The ictal EEG shows that the myoclonus correlates with the 3 Hz spike-wave discharges. In the syndrome of epilepsy with myoclonic absences, a different type of myoclonus pattern (“myoclonic absences”) is seen.22
Myoclonic absences have an impairment of consciousness. The myoclonus takes the form of jerking upper extremities initially, but then tonic EMG contraction of the proximal muscles causes arm elevation in addition to the jerking. The head and lower limbs may be involved as well. Some asymmetry in the myoclonus may occur. The 3 Hz spike-wave EEG discharges usually begin before the myoclonus, and the jerking movement correlates with the individual spike-wave discharges. Seizure duration may be 10 to 60 seconds. Epilepsy with myoclonic absences is often associated with other seizure types and has a worse overall prognosis than childhood absence epilepsy.23
Myoclonic seizures occur in about 11 to 28% of cases of Lennox-Gastaut syndrome.24 In myoclonic astatic epilepsy, myoclonic and/or myoclonic-astatic seizures occur in 100%, and multiple other seizure types can coexist. The myoclonic seizures in both syndromes are similar. The myoclonic seizures are generalized myoclonic jerks with a characteristic flexion of the head. The ictal EEG of myoclonic seizures shows generalized irregular polyspikes and spikes. Severity of the movement may vary considerably. Myoclonic-astatic seizures manifest a loss of muscle tone preceded by generalized myoclonic jerks with a characteristic flexion of the head (Video 16-1). The ictal EEG of these seizures shows 2 to 3 Hz spike and slow-wave discharges (Figure 16-2). Valproate, topiramate, zonisamide, lamotrigine, and clonazepam are commonly used treatments.25
Figure 16-2.
Electroencephalogram (EEG) showing slow spike and wave discharges (<3 Hz). The first discharge does not produce a myoclonic jerk. The second discharge produces a brief myoclonic-astatic seizure. Video 16-1 shows the characteristic myoclonic jerk with arm elevation and head nod in a patient diagnosed with Lennox-Gastaut syndrome.
Severe myoclonic epilepsy of infants (SMEI) is a rare disorder that begins in infancy with generalized and unilateral clonic seizures.26 These seizures are often triggered by fever, and other seizure types that are associated with myoclonus follow. Delay in development and inadequate response to antiseizure medication are typical. The prevalence of sodium channel (SCN1A) gene mutations in SMEI varies in studies from 33 to 80%.27 The myoclonic seizures seen are usually generalized with axial muscle involvement. Most commonly, they are associated with >3 Hz spike-wave discharges on the EEG for 1 to 3 sec.28 Besides myoclonic seizures, children with SMEI experience multifocal myoclonus that is increased with movement but without gross EEG accompaniment. It is not known whether back-averaging yields a focal cortical correlate for this multifocal myoclonus.
Several families have been described with certain core features: (1) distal activation rhythmic small-amplitude myoclonus (tremor) produced by EMG discharges exhibiting a cortical physiology, usually with enlarged SEP and enhanced long-latency EMG reflexes at rest (cortical reflex myoclonus); (2) infrequent, (secondarily) generalized tonic-clonic seizures; (3) autosomal dominant inheritance; and (4) a relatively benign course with normal cognition.29,30 Frequent seizures, other seizure types, larger arrhythmic myoclonic jerks, and abnormal cognition may occur in some patients. The term cortical tremor is usually meant to reflect the repetitive and rhythmic nature of the cortical myoclonus. However, some researchers find this confusing and prefer the term myoclonus. There have been various syndrome labels that have been used for this entity, but it has been determined that a main common phenotype exists for all of these syndromes.29,30
In this variety, the myoclonus is the most prominent or only clinical finding. Thus, it is an almost isolated or “essential” phenomenon, from which the patient usually experiences some, even if mild, disability. Essential myoclonus etiologies may be either sporadic or hereditary. Clinical progression is slow or not at all.7 Cognition is normal. Cases of sporadic essential myoclonus are heterogeneous with regard to distribution, what exacerbates the jerks, and other examination findings.31 Sporadic essential myoclonus probably consists of various heterogeneous, yet undiscovered causes of myoclonus and cases with false-negative family histories.
The differentiation of essential myoclonus syndromes from epilepsy is usually not difficult. Seizures are not seen in essential myoclonus. The jerks in essential myoclonus are persistently present without a paroxysmal nature. The EEG is normal, both in terms of epileptic discharges and the absence of slow-wave abnormalities.
Palatal myoclonus has been considered by some to represent tremor rather than myoclonus. Because some cases better resemble myoclonus, whereas others appear as tremor, the entity is considered here for completeness. Essential palatal myoclonus is usually caused by contractions of the tensor veli palatini, symptomatic palatal myoclonus is usually caused by the levator veli palatini, and middle ear myoclonus is caused by contractions of the tensor tympani and/or stapedius muscles.32–35 These conditions may cause tinnitus or ear clicking.36–38 Essential palatal myoclonus demonstrates segmental myoclonus physiology.
Hereditary essential myoclonus is clinically characterized by (1) onset before age 20 years; (2) dominant inheritance with variable severity; (3) a benign course compatible with an active life and normal longevity; and (4) the absence of cerebellar ataxia, spasticity, dementia, and seizures.39 The myoclonus is usually distributed throughout the upper body, exacerbated by muscle activation, and dramatically decreased with alcohol ingestion. The term myoclonus-dystonia syndrome has been introduced because of the common occurrence of dystonia in these cases.
Mutations in the ε-sarcoglycan gene on chromosome 7q21 have a strong association with hereditary essential myoclonus, with two thirds of patients exhibiting dystonia (myoclonus-dystonia syndrome).40 Hereditary essential myoclonus demonstrates subcortical-nonsegmental myoclonus physiology. The electrophysiological features of patients with the ε-sarcoglycan mutation have been described.41 These myoclonic jerks show a mean EMG duration of 95 msec, with a range of 25 to 256 msec. There are no signs of cortical excitability, including a lack of a back-averaged premyoclonus correlate, enlarged cortical SEPs, or enhanced long-latency EMG reflex.
In this clinical category, myoclonus manifests as a symptom secondary to a neurologic or nonneurologic disorder. The range of disorders causing symptomatic myoclonus is quite large. It includes storage disorders, neurodegenerative diseases, drug-induced and toxic-metabolic conditions, inflammatory disorders, and various insults or injuries to the brain. There is often clinical or pathologic evidence of diffuse nervous system involvement. Multiple significant clinical manifestations exist in these patients and may be even more prominent than the symptom of myoclonus. Mental status abnormalities, ataxia, and other movement disorders are common clinical associations in symptomatic myoclonic syndromes. Chronic or subacute clinical progression suggests symptomatic myoclonus, but other presentations are common. The cortex is the most commonly proven source of the myoclonic jerks.
The distinction of symptomatic myoclonus disorders from epilepsy can be more difficult to make than the distinction of essential myoclonus disorders. Symptomatic myoclonus etiologies can give rise to seizures. However, the clinical picture is dominated by myoclonus that is induced by action, stimuli, or rest, rather than by myoclonus that is unpredictable or paroxysmal. Most, but not all, symptomatic myoclonus cases exhibit a cortical physiology and much less commonly subcortical, cortical-subcortical, segmental, or peripheral physiology. Different body distributions are possible, and none is typical. Unlike seizures, back-averaging is usually necessary to establish an EEG correlate to the myoclonus generation in symptomatic myoclonus.
A subset of genetic metabolic disorders and certain other conditions commonly present their myoclonus within the syndromes of progressive myoclonic epilepsy (PME) and progressive myoclonic ataxia (PMA). Main syndrome components of PME are seizures, myoclonus, ataxia, and sometimes dementia; furthermore, PME may lead to severe mental impairment and death. The progressive nature of the illness and cognitive decline differentiate PME diagnoses from more benign epileptic syndromes. Lafora body disease is a prime example of a PME syndrome that is dominated by seizures, dementia, and myoclonus. However, other disorders that have historically been classified as PME probably better fit a related syndrome of PMA, where ataxia and myoclonus are the more prominent or sole components.42 In PMA, there is a much slower clinical progression. Sialidosis, Unverricht-Lundborg syndrome, and mitochondria disorders are more likely to present with a PMA syndrome than PME. Coeliac disease, a malabsorption syndrome, presents as PMA. The myoclonus physiology demonstrated in these disorders is cortical action and/or cortical reflex myoclonus.
In Unverricht-Lundborg syndrome, a mutation has been found in the cystatin B (EPM1) gene. The electrophysiology of the multifocal myoclonus in an individual with the EPM1 mutation is shown in Figures 16-3 and 16-4. The findings demonstrate a cortical physiology with a back-average focal EEG premyoclonus transient and enlarged cortical SEP. Video 16-2 demonstrates frequent myoclonic jerking that evolves into a generalized myoclonic-tonic-clonic seizure. Figure 16-5 shows the evolving EEG coinciding with the event.
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