Myoclonus

Parkinsonism & Related Disorders Parkinsonism and Related Disorders 13 (2007) S375–S384 www.elsevier.com/locate/parkreldis

Myoclonus John N. Caviness* Mayo Clinic, Scottsdale, AZ, USA

Abstract Myoclonus has now been recognized to have many possible etiologies, anatomical sources, and pathophysiologic features. Classification schemes may be based on clinical syndromes and etiology, neurophysiology properties, or exam findings. In recent years, many myoclonus case reports and short series have been published. However, this article will group new developments into three areas: (1) Myoclonus in parkinsonian disorders, (2) Concepts in myoclonus generation, and (3) Treatment. Current findings do not allow one to conclude whether or how parkinsonism contributes to the myoclonus mechanism in parkinsonian disorders. Therefore, it seems unlikely that the myoclonus in Lewy body disorders is mostly caused by abnormal basal ganglia input to motor areas of the neocortex. The exact source of cortical myoclonus generation is controversial. Increased corticomuscular coherence represents a robust phenomenon that will need to be explained by any model that offers a putative explanation for cortical myoclonus generation. Myoclonus treatment is still limited, and more research on basic mechanisms before truly effective treatment will be available. The best approach for myoclonus is based on the physiological classification of the myoclonus. © 2007 Elsevier B.V. All rights reserved. Keywords: Myoclonus; Cortex; Neurophysiology; Epilepsy

1. Introduction 1.1. Clinical classification Myoclonus is a clinical symptom (or sign) defined as sudden, brief, shock-like, involuntary movements caused by muscular contractions or inhibitions. Myoclonus has now been recognized to have many possible etiologies, anatomical sources, and pathophysiologic features [1]. When including all known etiologies, myoclonus has an average annual incidence of 1.3 cases per 100,000 [2]. The major categories of myoclonus in the popular etiological classification scheme of Marsden et al. [3] are as follows: physiologic, essential, epileptic, and symptomatic (secondary). The individual disorders/conditions that are listed for each major category have been published many times [1,3]. Each of the major categories is associated with different clinical circumstances. Physiologic myoclonus occurs in neurologically normal people. There is minimal or no associated disability and the physical exam reveals no relevant abnormality. Jerks during sleep are the most familiar examples of physiologic myoclonus. Essential myoclonus refers to myoclonus that is the most prominent or only clinical finding. Essential myoclonus is idiopathic and progresses slowly or not at * Correspondence: John N. Caviness, M.D. Professor of Mayo Clinic College of Medicine, Mayo Clinic, Department of Neurology, 13400 East Shea Blvd., Scottsdale, AZ 85255, USA. Tel.: +1 480 301 6328; fax: +1 480 301 8451. E-mail address: [email protected] (J.N. Caviness). 1590-8658/ $ – see front matter © 2007 Elsevier B.V. All rights reserved.

all. Sporadic and hereditary forms exist, and some families manifest a genetic mutation. Epileptic myoclonus refers to the presence of myoclonus in the setting of epilepsy – that is, a chronic seizure disorder. Myoclonus can occur as only one component of a seizure, the only seizure manifestation, or one of multiple seizure types within an epileptic syndrome. Symptomatic (secondary) myoclonus manifests in the setting of an identifiable underlying disorder, neurologic or non-neurologic. Mental status abnormalities and ataxia are common clinical associations in symptomatic myoclonic syndromes. Symptomatic causes of myoclonus comprise a widely diverse group of disease processes and include neurodegenerative diseases, storage diseases, toxic-metabolic states, physical processes, infections, focal nervous system damage, and paraneoplastic syndromes as well as other medical illnesses. Most clinically relevant cases of myoclonus are in the symptomatic category, followed by the epileptic and essential categories. 1.2. Physiological classification Etiological classification provides a framework to match a patient’s myoclonus to an etiology from a comprehensive list of disorders. However, there are at least four advantages to classifying the myoclonus with regard to its physiology. First, physiology can provide localizing information for the myoclonus and thus can provide at least partial localization for diagnosis of the underlying process. Second, some phys-

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Fig. 1. EEG–EMG back-averaging of the right wrist extensor group muscles in a patient with myoclonus. The back-averaged focal EEG correlate over the left sensorimotor cortical area (electrode C3) provides evidence for a cortical source generating the myoclonus. In the lower left area of the figure, the averaged myoclonus EMG discharge from the right wrist extensor group muscles is seen. The positive deflection preceding the myoclonus EMG discharge is 15−20 ms before the onset of the myoclonus EMG discharge, consistent with conduction along the corticospinal pathway.

iological myoclonus types are characteristic for certain disorders, so identifying their presence can aid in identifying the underlying diagnoses. Third, ascertaining the physiology of the myoclonus directs the physician toward the most effective treatment [1,4]. Finally, comparing and contrasting the myoclonus physiology in various disorders provides insights about the disease processes that create them [4]. The specific methods used in the neurophysiological study of myoclonus usually include but are not limited to multichannel surface electromyography (EMG) recording with testing for long latency EMG responses to mixed nerve stimulation, electroencephalography (EEG), EEG–EMG polygraphy with back-averaging, and evoked potentials (e.g. median nerve stimulation somatosensory evoked potential [SEP]). Positive and negative findings from these methods can then be used to provide evidence for determining the physiological type of myoclonus [5]. For example, a back-averaged focal cortical EEG transient, enlarged cortical SEP, and enhanced long EMG responses suggest cortical origin myoclonus [4]. The main physiological categories for myoclonus classification are: • Cortical – most common, and has been reported for various neurodegenerative diseases, toxic-metabolic conditions, post-hypoxic state (Lance-Adams syndrome), storage disorders, and other conditions. An example of cortical myoclonus physiology is shown in Figure 1. • Cortical–subcortical – corresponds to the myoclonus in myoclonic and absence seizures. This physiology is believed to involve interactions of cortical and subcortical centers such as the thalamus.

• Subcortical–suprasegmental – seen in essential myoclonus and reticular reflex myoclonus, among others. • Segmental – arise from segmental brainstem (palatal) and/or spinal generators. • Peripheral – except for hemifacial spasm, peripheral myoclonus is rare. One should be aware that multiple myoclonus physiology types could occur in the same patient. A recently described myoclonus symptom was coined “orthostatic myoclonus” [6]. Orthostatic myoclonus occurs during leg muscle activation with an upright posture. These reported patients usually had gait deterioration resembling gait ignition failure or gait apraxia. This myoclonus symptom occurred sometimes alone but most often with associated diseases or conditions. The origin of orthostatic myoclonus is not known. 1.3. Evaluation Both the properties of the myoclonus and the other aspects of the clinical presentation determine what type of testing should be done [1]. For example, if an infectious or inflammatory syndrome is present, a cerebrospinal fluid exam should be done. Knowledge of the various diagnostic entities in will facilitate the proper diagnostic confirmation. The following minimal testing should be done in all unexplained cases of myoclonus: Electrolytes Drug and toxin screen Glucose Brain imaging Renal function tests Electroencephalography Hepatic function tests

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If these tests do not reveal the diagnosis, then more advanced testing should be considered. Additional testing may include clinical neurophysiology testing, cerebrospinal fluid examination, enzyme activity, paraneoplastic testing, other metabolic testing, and other tests [1]. In some cases, genetic testing may be considered. Before genetic testing is done, the patient should be fully aware of the implications for both positive and negative results. If appropriate, genetic counseling is recommended. 1.4. Updates in myoclonus In recent years, many myoclonus case reports and short series have been published. However, this article will group new developments into three areas: (1) Myoclonus in parkinsonian disorders, (2) Concepts in myoclonus generation, and (3) Treatment.

2. Myoclonus in parkinsonian disorders 2.1. Introduction Myoclonus occurs in several parkinsonian disorders. These disorders range from those with moderately severe parkinsonism to those that can have mild parkinsonism associated with relatively more significant non-parkinsonian features. Most all of the disorders are neurodegenerative, and at initial presentation affect different brain locations clinically and pathologically. The chronic progression in these disorders results in more clinical phenomena and diffuse pathological changes. The myoclonic jerks may present small, then grow in size or spread in distribution or both. Many of these disorders include cognitive dysfunction. A disorder that combines myoclonus and parkinsonism readily identifies itself as belonging to the symptomatic myoclonus category of the clinical classification scheme of Marsden et al. Current evidence suggests that the myoclonus mechanism differs across these different parkinsonian syndromes. Moreover, different types of myoclonus in the same syndrome may occur. Because of these observations and other reasons discussed in this article, it is difficult to know whether the parkinsonism in these disorders is linked to the myoclonus mechanism. Nevertheless, it is clinically useful to group these disorders. The presence of parkinsonism and myoclonus in a patient suggests a differential diagnosis list that may be navigated towards a working diagnosis and treatment. 2.2. Lewy body disorders Parkinson’s disease The occurrence of moderate- or large-amplitude myoclonus as an initial presentation with parkinsonism is much more consistent with a non-PD diagnosis. However, smallamplitude myoclonus has been described to occur in idiopathic Parkinson’s disease [7]. Since the myoclonus in

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PD usually has small amplitude and is repetitive with tonic muscle activation, it can be confused with tremor. Druginduced myoclonus in Parkinson’s will be discussed in the subsection on “Medications and tardive syndromes” below. The rest of this discussion will focus on myoclonus in PD not secondary to another cause or diagnosis. We have described small-amplitude cortical myoclonus (SACM) in non-demented Parkinson’s disease (PD) individuals, one of whom was pathologically verified as PD [7]. Subsequently, three more myoclonus cases in our brain bank have been verified to be Lewy body PD. The myoclonus is characteristically positive, being produced by 20−40 ms EMG discharges. Myoclonus EMG discharges may occur in an agonist-only pattern, or spread to antagonist and contiguous limb segments by showing a co-contraction pattern of the other muscles involved. EEG–EMG backaveraging consistently shows a focal, short latency, EEG transient prior to the myoclonus EMG discharge [7]. Most cases show sporadic small and infrequent myoclonic jerks of the fingers and wrist during postural activation. However, in many cases, frequent (
6 Hz) repetitive rhythmic trains of EMG discharges coincide with movements that appear similar to tremor or as irregular movement that interrupt a small-amplitude postural tremor. When the myoclonus EMG discharges are small and higher frequency, the lowpass frequency properties of muscle electromechanical transduction may decrease the amplitude to a difficult to detect level. In other words, the surface EMG appearance of these discharges can be more dramatic than the amplitude of the myoclonus per se. Negative myoclonic movements can occur and have the properties of “Type III negative myoclonus”, which shows a discrete positive myoclonus EMG discharge preceding the EMG silence that produces the negative myoclonus. The degree of parkinsonism, as measured by the United Parkinson’s Disease Rating Scale, does not correlate with the occurrence of myoclonus in PD, and advanced parkinsonism was not a requirement to manifest this type of myoclonus [7]. Although these cases were not demented, we have observed the subsequent development of dementia in a PD patient who was found to have this cortical myoclonus three years before becoming manifest. In the PD cases with SACM that have so far come to autopsy, Lewy bodies are found in the limbic system and neocortex as well as in the substantia nigra. Thus, it is possible that the cortical dysfunction that produces myoclonus has an association with the presence of Lewy bodies in neocortex. The clinical neurophysiology of this myoclonus suggests an origin in the sensorimotor cortex of these PD patients. These combined findings and observations suggest the possibility that the pathology within the sensorimotor cortex that produces the myoclonus is similar to pathology that when present in a diffuse distribution, may produce dementia in PD. More study is needed to confirm the underlying mechanism of the SACM in PD.

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Dementia with Lewy bodies Consensus criteria of dementia with Lewy bodies (DLB) include progressive cognitive decline resulting in impairment of daily functioning, 2 of 3 core features (parkinsonism, fluctuating cognition, visual hallucinations), and less frequent supportive features [8]. Myoclonus has been reported in about 15−20% of patients. This should be an underestimate of myoclonus prevalence in DLB since these data came from some cross-sectional data and retrospective reviews. Myoclonus in DLB usually arises from rest, muscle activation, or both. The myoclonus during muscle activation is characteristically more frequent than at rest, although both may be moderate amplitude. The distribution may be multifocal or generalized and affect any body part. However, the arms, neck, and face are the most common locations. The myoclonus in DLB has a cortical source with similar electrophysiological properties to those found in PD [9]. However, when compared to the SACM in PD, myoclonus in DLB is larger and more often detectable at rest [9]. Genetic Lewy body syndromes There are now multiple reports of families with genetic mutations that have Lewy bodies at autopsy [8]. Although some of these genetic disorders have been cited as genetic forms of DLB, myoclonus is not mentioned as a prominent feature [8]. In a family that was subsequently found to have an alpha-synuclein triplication with DLB pathology, cortical myoclonus with similar electrophysiology in to the myoclonus in DLB and PD was found [9]. Myoclonus across the spectrum of Lewy body disorders In summary, the myoclonus that has been described in PD, DLB, and hereditary Lewy body disorders has been found to have similar clinical and electrophysiological characteristics [9]. This suggests that there may be unifying causative mechanisms underlying the myoclonus in Lewy body disorders. When considering the disorders associated with myoclonus and Lewy body parkinsonism, it may be observed: (1) Parkinsonism severity does not correlate with the presence or severity of myoclonus. (2) Myoclonus is more prevalent and more severe in those disorders that have clinical and pathological evidence of neocortical pathology. For instance, myoclonus in DLB is more common and has higher amplitude than in PD. (3) When a source for myoclonus is localized, it is found in the sensorimotor neocortex. (4) Current findings do not allow one to conclude whether or how parkinsonism contributes to the myoclonus mechanism in parkinsonian disorders. Therefore, it seems unlikely that the myoclonus in Lewy body disorders is mostly caused by abnormal basal ganglia input to motor areas of the neocortex. One possible primary cortical mechanism for the cortical myoclonus production would be the lack of inhibitory

influences and/or excessive excitation produced by the neurodegeneration occurring locally in the sensorimotor cortex. On the other hand, neurochemical abnormalities and/or abnormal remote input from other areas may be playing a prominent role. More direct evidence is needed to elucidate this mechanism. Since the myoclonus in Lewy body disorders so far studied has had a cortical source, treating the myoclonus with agents that treat cortical myoclonus is reasonable, but no studies have documented a positive effect. Unless the myoclonus is causing significant additional disability to the parkinsonism and cognitive dysfunction, a treatment trial is of questionable value. 2.3. Corticobasal syndrome Myoclonus is an important feature of corticobasal degeneration and occurs in about 50% of cases. The clinical presentation parallels that of the overall syndrome with the myoclonus having a focal distribution in the arm (sometimes leg) associated with other focal limb manifestations that can include apraxia, rigidity, dystonia, cortical sensory deficits, and alien-limb phenomenon. When myoclonus first appears in corticobasal degeneration, it occurs in repetitive rhythmic fashion when an attempt is made to activate the arm. Reflex myoclonus to somatosensory stimulation is also very common. Later in course of the illness, spontaneous myoclonus occurs but may still be exacerbated by muscle activation and sensory stimuli. Multichannel surface EMG recordings in corticobasal degeneration show rhythmic repetitive trains of 25−50 ms discharges with simultaneous activation in agonist–antagonist pairs. The physiology in corticobasal degeneration shows a sensitive long latency EMG response to digital nerve stimulation at about 50 ms, whereas median nerve stimulation has a response about 40 ms. The SEP is either unremarkable or can be altered in morphology without enlargement. There has been a cortical correlate back-averaged from magnetoencephalography for this myoclonus, but no backaveraged activity detected with EEG is characteristic. These myoclonus electrophysiology characteristics are very different from classical cortical reflex myoclonus. Corticobasal degeneration is known as a sporadic tau disorder. The tau pathology has a strong presence in frontoparietal areas and this could serve as a substrate for the myoclonus generation. Treatment of the myoclonus in corticobasal syndrome is notoriously difficult. Levodopa will relieve parkinsonism in some patients, but it does not treat the myoclonus. By anecdotal evidence, clonazepam is the agent most known to be effective for the myoclonus in corticobasal degeneration. Clonazepam only works in a minority of cases and side effects, such as drowsiness, are limiting. Even if the myoclonus responds to treatment, the limb often remains disabled by apraxia and rigidity.

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2.4. Multiple system atrophy There is agreement that myoclonus occurs in multiple system atrophy (MSA), but there are differing views on many aspects of the myoclonus. Similar to corticobasal syndrome, postural tremor in MSA has been linked to the myoclonus but the nature of the connection differs among reports in the extant literature. Upper extremity small-amplitude “jerky postural tremor” is seen in 20−55% of cases. Salazar et al. argued both on clinical and electrophysiological grounds that the “jerky postural tremor” movements were best characterized as myoclonus rather than tremor [10]. They found such movements in 9/11 or 82% of their parkinsonian type multiple system atrophy cases. The varied phenomenology of postural muscle activation in MSA points out the challenge in distinguishing tremor from small repetitive myoclonus occurring within the typical tremor frequency range. The notion that the postural tremor in MSA may evolve into postural myoclonus as the neurodegeneration progresses is an interesting but unproven possibility. In the cerebellar presentation of MSA, the electrophysiology of the somatosensory stimulus-sensitive myoclonus has shown reflex EMG activation consistent with a transcortical conduction time and enlarged cortical components of the SEP. Because of these observations, the myoclonus origin was proposed to be cortical. In their cases of minipolymyoclonus during postural activation, Salazar et al. found EMG discharges with less than 100 ms duration, enhanced long latency EMG responses to cutaneous stimulation at 50−63 ms, and normal SEP and EEG. Backaveraging of 50 samples of the myoclonus demonstrated no back-averaged cortical correlate. As a result, Salazar et al. were uncertain with regards to the origin of the myoclonus [10]. However, Okuma et al. [11] found cocontraction of agonist–antagonist myoclonus EMG discharges during postural activation, mild SEP enlargement in some cases, and enhanced premyoclonus EEG potentials in 9 of their MSA patients. They suggested a cortical origin for the myoclonus [11]. There is very little information about the treatment of myoclonus in MSA. Since both somatosensory stimulussensitive and postural activation myoclonus appear to have a cortical origin, it is possible that cortical myoclonus treatments such as clonazepam or levetiracetam may be effective. However, the myoclonus in MSA causes relatively little disability compared with the parkinsonism, ataxia, and autonomic problems. This should be kept in mind for any consideration to start anti-myoclonus therapy.

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PSP, action myoclonus with seizures showed myoclonus EMG discharges of <50 ms duration. The myoclonus EMG discharges grossly correlated with EEG epileptiform activity, but a time-locked analysis was not done. The pathology, indicative of PSP, was present in the cerebral cortex in addition to the more typical subcortical distribution. Palatal myoclonus has also been reported in a case of PSP. More examples of myoclonus in autopsy-confirmed PSP need to be characterized before any generalization can be formulated. 2.6. Dentato-rubro-palatal-luysian atrophy (DRPLA) This neurodegenerative disorder is associated with a CAG repeat expansion in a gene on chromosome 12. DRPLA has protean neurologic manifestations that are variable both within and between families, including chorea, dystonia, parkinsonism, epilepsy, psychosis, and dementia. The myoclonus in dentato-rubro-pallido-luysianatrophy is uncommon but usually associated with epilepsy. A cortical source seems likely for the myoclonus because of associated epileptiform activity on the EEG, but detailed electrophysiological examination of the myoclonus has not been reported. 2.7. Frontotemporal dementia linked to chromosome 17 (FTDP-17) Although not initially thought to be a prominent feature, myoclonus has now been described in some FTDP-17 syndromes. These syndromes, associated with tau gene mutations, manifest cognitive, psychiatric, and parkinsonian symptoms. Myoclonus is rarely seen in FTDP-17 kindreds but has been reported with the N279K, P301S, and V337M tau mutations, and a different family with the P301S mutation has seizures. We have described two types of myoclonus physiology in pallido-ponto-nigral degeneration (PPND) which has been associated with the N279K tau mutation. The absence of a back-averaged EEG transient characterized the myoclonus physiology associated with disease progression, whereas a pre-myoclonus EEG transient was present in the myoclonus that occurred in one of the individuals with Stage 0 (pre-symptomatic, gene positive). FTDP-17 syndromes commonly have cortical and subcortical pathology. The precise mechanism of the myoclonus types seen in FTDP-17 syndromes is unclear, but it has been suggested that pathology in the frontoparietal area is more predisposed to myoclonus degeneration than frontotemporal pathology.

2.5. Progressive supranuclear palsy

2.8. Huntington’s disease

Progressive supranuclear palsy (PSP) is another sporadic tau disorder, but in contrast to corticobasal degeneration, myoclonus has only been rarely mentioned in the context of PSP. Myoclonus has been rarely ascribed to progressive supranuclear palsy. In one case of autopsy-confirmed

The occurrence of myoclonus is unusual in Huntington’s disease, but when present, can be clinically impressive. The myoclonus is usually restricted to individuals with a young age of onset and higher CAG repeat mutation values. Seizures and parkinsonism may be present. The

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physiology of the myoclonus is consistent with cortical reflex myoclonus, although the cortical SEP waves are rarely enlarged. Presumably, in older cases with lower CAG repeat mutation values and slower progression, the cortical pathology is much less significant when compared to the rapidly progressive young-onset Huntington’s disease cases, thus enabling the myoclonus to occur in the youngonset cases. 2.9. Post-encephalitic parkinsonism The encephalitis lethargica epidemic, which eventually occurred all over the world in the first part of the twentieth century, was hypothesized to be viral although the exact agent is controversial. Post-encephalitic parkinsonism was a disabling complication that occurred in more than 60% of encephalitis lethargica patients and had an average age of onset around 27 years. Along with parkinsonism, these cases could have an amazing array of hyperkinetic movement disorders, including myoclonus. It was common that myoclonus accompanied the parkinsonism. The myoclonus appearance was variable. It could be rhythmic or arrhythmic, generalized or focal in any part of the body. Myoclonus of the abdomen was somewhat characteristic. 2.10. Medications and tardive syndromes Myoclonus at rest during relaxation and sleep can be secondary to levodopa. This was reported initially in the pre-carbidopa era, when very high doses of levodopa had to be used because of excessive metabolism in the periphery. Although this myoclonus was subsequently reported at lower levodopa doses in carbidopa/levodopa preparations, it has always occurred in the higher levodopa dose range and it decreased or disappeared at lower doses. The myoclonus was usually generalized but could also just affect one side or one limb. The jerks may or may not wake the patient up. Generalized EEG transients have been recorded with this myoclonus but the significance of this observation is unknown. At first, it was proposed that levodopainduced myoclonus was due to serotonin dysregulation. Subsequently the dopamine agonist bromocriptine was reported to cause the same myoclonus phenotype in the same patients. The authors proposed that this indicated a direct dopaminergic receptor effect for the mechanism of the myoclonus. Dopamine antagonists, most notably the neuroleptics, have been associated with myoclonus that occurs in the neck, shoulders, and proximal upper extremities. In addition, the myoclonus may present acutely after drug initiation or appear years later as a tardive phenomenon. However, parkinsonism is not associated more with myoclonus cases versus non-myoclonus cases. Thus, the mechanism of dopamine antagonist induced myoclonus remains to be clarified.

2.11. Alzheimer’s disease The myoclonus in Alzheimer’s disease has a varied presentation profile. It is usually multifocal, although it can be generalized. Parkinsonism, like myoclonus, is commonly present in those with Alzheimer’s disease, particularly in later stages. The appearance can be sporadic large myoclonic jerks or repetitive small ones. The occurrence of the jerks may be at rest, with action, or stimulus induced. It is common for all the above-mentioned phenotypic characteristics to occur in a single patient. The prevalence of myoclonus increases steadily during disease progression, and up to 50% of Alzheimer’s disease patients eventually develop myoclonus. Although myoclonus often develops in the later stages of the illness, an earlier age of Alzheimer’s disease onset, faster progression, or familial causes of Alzheimer’s disease are associated with myoclonus appearing earlier and at a higher incidence. In a paper by Wilkins et al. [12], a few examples of myoclonus in Alzheimer’s disease were described as minipolymyoclonus, i.e. small-amplitude repetitive myoclonus occurring distally in the upper extremities. In the same article, these authors acknowledge the overlap with tremor. Multiple different electrophysiological descriptions of the myoclonus in Alzheimer’s disease have been reported. The most commonly reported instance is myoclonus EMG discharges <100 ms duration, and a focal contralateral central EEG negativity, with onset 20−40 ms pre-myoclonus and duration 40−80 ms. 2.12. Creutzfeldt–Jakob disease The myoclonus in Creutzfeldt–Jakob disease can occur in early, middle, or late stages. Its clinical presentation can vary, and focal, multifocal, or generalized jerks may occur. Accompanying the rigidity, parkinsonism can be associated with this disorder. The jerks can be rhythmic or arrhythmic, and stimulus sensitivity (somatosensory, startle, light) is common. The gross EEG findings of an abnormal slow and/or suppressed background and generalized periodic sharp wave discharges are well known. The EMG duration is <50 ms and an agonist-only pattern or with co-contraction in antagonists and other muscles is observed. There is a variable correlation between the timing of the myoclonus and the sharp wave discharges on routine EEG. When back-averaging is used, a broadly distributed contralateral negative transient is seen. This EEG correlate has 100–160 ms duration and a latency to the myoclonus EMG discharge of 50−85 ms. Enlargement of the cortical SEP waves and enhanced long latency reflexes is variable. A photic cortical reflex myoclonus physiology has also been described in patients with Creutzfeldt–Jakob disease. 3. Concepts in myoclonus generation In previous decades, myoclonus was characterized as a lack of inhibition in neuronal circuits. Although this must

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be correct at some level, this physiological explanation of myoclonus is too simple and general to provide a full explanation of how myoclonus is generated. In recent years, some new concepts have been introduced which try to enhance our understanding of how myoclonus is generated. Recent concepts in myoclonus generation will be divided by the methods employed: (1) magnetoencephalography, (2) coherence studies, (3) other electrophysiology methods, (4) genetic studies, and (5) histochemical studies. 3.1. Magnetoencephalography Magnetoencephalography (MEG) has the ability to perform better localization and amplitude sensitivity (horizontal dipoles) when compared to EEG. Uesaka et al. [13] found that among six subjects with cortical myoclonus and one with epilepsia partialis continua: (1) the dipole was located at the precentral gyrus in the case with epilepsia partialis continua, (2) dipoles were present both on the precentral and postcentral gyrus in a cortical myoclonus case, and (3) five cases localized to the postcentral gyrus only. In this study, the initial cortical somatosensory evoked magnetic fields localized to the postcentral gyrus. Uesaka et al. suggested that patients with enlarged SEPs are likely to have myoclonus arise from the postcentral gyrus. In contrast, Mima et al. [14] found the MEG cortical correlate for all six of their myoclonus subjects to localize to the precentral gyrus. In another report, Mima et al. [15] found that enlarged cortical somatosensory evoked magnetic fields localized to the precentral gyrus in four subjects and to the postcentral gyrus in one subject. More studies will be needed to sort out whether these separate studies actually conflict or if case to case variability can truly be seen in cortical myoclonus. 3.2. Coherence studies Brown et al. have found changes in EEG–EMG and EMG–EMG coherence patterns for subjects with myoclonus [16]. They have suggested that myoclonus patients show pathological exaggerations of physiological central rhythmicity relating to movement and that the precise pattern of coherence has possible diagnostic value. In some cases, elevated coherence is more sensitive than EEG– EMG back-averaging. Subsequently, others found elevated corticomuscular coherence in cortical myoclonus. Diseases and conditions that have demonstrated elevated corticomuscular coherence with myoclonus include post-hypoxic myoclonus, celiac disease, progressive myoclonic epilepsies, progressive myoclonic ataxia syndrome, Angelman’s syndrome, Lewy body disorders including Parkinson’s disease, Lennox–Gastaut syndrome, autosomal dominant cortical reflex myoclonus and epilepsy syndrome, and HIV encephalopathy. In the myoclonus of corticobasal degeneration, no elevated corticomuscular coherence was found. These findings represent a robust phenomenon that will need to be explained by any model that offers a putative

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explanation for cortical myoclonus generation. In addition, local field potentials in the globus pallidus have been found to show coherence with muscular activity in myoclonus– dystonia syndrome which is believed to have its abnormality in subcortical regions. 3.3. Other electrophysiology methods Electrodes placed on the cortical surface are used extensively in epilepsy surgery, but there are only rare opportunities to do this in myoclonus. Ashby et al. [17] analyzed cortical recordings in a case of severe myoclonus associated with coeliac disease. The myoclonus origin as well as the enlarged SEP wave was localized to the motor cortex. In another study, Hitomi and colleagues [18] showed that both primary sensory and motor cortex generated enhanced early cortical components of SEPs in cortical reflex myoclonus, most likely by the latter enhancing the former. 3.4. Genetic studies The discovery of a genetic mutation as a cause for a myoclonus syndrome offers the opportunity of linking molecular events with neuronal circuit disruption and myoclonus pathophysiology [19]. Several types of gene mutations have been associated with myoclonus syndromes. However, it has been difficult to link a specific mutation with a neuronal circuit abnormality that generates myoclonus. This is because the pathology caused by the mutation is diffuse within the central nervous system. Moreover, different physiologic types of myoclonus probably arise from different neuronal circuit abnormalities, so that the implicated circuit abnormality from one mutation may not have relevance to another (e.g. Cystatin B for cortical myoclonus versus epsilon-sarcoglycan gene for subcortical myoclonus). Finally, these gene mutations are usually causing multiple symptoms and not just myoclonus. Genetic defects in myoclonus should be pursued, but other data will be needed to pinpoint how a specific genetic mutation causes a particular type of myoclonus. 3.5. Histochemical studies Studies on central nervous system tissue have been largely limited to animal models of myoclonus. Most recent studies have been performed on the rat model of Truong and colleagues [20]. In this model, areas that undergo neuron degeneration include the cortex, thalamus, cerebellum, and brainstem. Biochemical studies show decreased serotonin measures. The serotonin precursor 5-hydroxytryptophan treats the myoclonus of this animal model. Levetiracetam and brivacetam, among other agents, also decrease the myoclonus. Truong and colleagues believe that the myoclonus generated in this model is due to multiple levels of the brain [20].

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3.6. Summary

4.1. Cortical myoclonus treatment

Studies suggest that abnormal sensorimotor cortex function is involved in the generation of cortical myoclonus. However, the relative roles of primary sensory versus primary motor cortex may not be the same across all cases of cortical myoclonus. Abnormalities of central rhythms over the sensorimotor cortex are operant in cortical myoclonus, but it is not known what neuronal circuitry defect specifically produces the elevated corticomuscular coherence in cortical myoclonus. None of these concepts rule out involvement of subcortical structures, and historically the cerebellar system has been suggested to play a role in cortical myoclonus generation. Evidence from animal models and humans suggests that there may be multiple sites in the central nervous contributing to myoclonus, and there are several ways to produce myoclonus from a physiological point of view.

Drug treatment is primarily aimed at augmenting deficient inhibitory processes within the sensorimotor cortex [1]. Levetiracetam and piracetam, sodium valproate, and clonazepam are the four most effective agents used. However, many patients only gain adequate relief from their myoclonus when drugs are used in combination. Gait disturbance tends to be the most resistant feature and a bouncy unsteady gait with frequent falls may persist despite better control of action and reflex myoclonus in the upper limbs.

4. Treatment The most ideal strategy for the treatment of myoclonus is, of course, the treatment of the underlying disorder. Some causes of myoclonus can be reversed partially or totally, such as an acquired abnormal metabolic state, removal of a medication or toxin, or an excisable lesion. There is some evidence that psychogenic jerks respond to psychotherapy and pharmacological psychiatric treatment. However, in the majority of myoclonus cases, treatment of the underlying disorder usually is not possible or effective, and symptomatic treatment is justified if the myoclonus is disabling enough. An approach to symptomatic treatment ideally is derived from its myoclonus physiological classification. This is because an agent or treatment strategy for one physiological mechanism may not work well in another, does not work at all, or may even cause worsening. If the myoclonus physiology classification can not be determined, then presuming the myoclonus physiology that usually occurs in that diagnosis is a reasonable way to cautiously proceed. If the diagnosis and myoclonus physiology are unknown, the treatments under the cortical myoclonus physiology classification can be tried first since cortical myoclonus physiology is the most common. Multiple drug trials are sometimes necessary to find the best drug for a certain patient. Myoclonus treatment is often unsuccessful from the viewpoint of the patient. High expectations for a marked decrease or total elimination in the myoclonus are usually unrealistic. No drug has been manufactured for the specific purpose of treating myoclonus thus far. As a result, there is sparse controlled evidence on the treatment of myoclonus. Side effects are commonly dose-limiting. The discussion of treatment below is outlined under the physiological classification of the myoclonus [1].

Levetiracetam and piracetam Levetiracetam and piracetam are related drugs and have had limited controlled study. Their mechanism of action remains unknown. Both are well tolerated and generally non-sedating. Because of their relatively favorable side effect profile, these drugs can be used initially or as addon treatment. Anecdotal reports for levetiracetam responsiveness in specific etiologies of cortical myoclonus exist for Unverricht–Lundborg disease, Myoclonus Epilepsy with Red Ragged Fibers (MERRF) syndrome, negative myoclonus, Creutzfeldt–Jakob disease, in addition to posthypoxic myoclonus and various progressive myoclonic epilepsy syndromes. Therapeutic daily dosages of piracetam range between 2.4 g and 21.6 g and for levetiracetam range between 1000 mg and 3000 mg. An abrupt withdrawal may precipitate a severe worsening of myoclonus and in the case of piracetam, seizures may occur. Sodium valproate The drug is introduced slowly, with most patients needing doses of 1200 to 2000 mg/day. Transient gastrointestinal upset may occur during initial treatment, usually with nausea and vomiting, but sometimes with abdominal pain and diarrhea. Hair loss, tremor, hepatotoxicity, and drowsiness may also occur. Clonazepam Large doses of clonazepam are often necessary (as much as 15 mg/day) but should be introduced slowly. Undue drowsiness and ataxia are the only major side-effects and can be sometimes overcome by gradually increasing the dosage. Abrupt reductions and withdrawals can result in a marked deterioration in myoclonus and withdrawal seizures. Tolerance may develop over a period of several months in some patients. Other agents Primidone and phenobarbital are occasionally useful. Phenytoin and carbamazepine are helpful in only a minority of patients. In others, particularly those with Unverricht– Lundborg disease, phenytoin may exacerbate myoclonus. Zonisamide has helped in some cases. Vigabatrin, an irreversible inhibitor of GABA transaminase, surprisingly does not seem very useful. It may lead to a paradoxical increase in myoclonus in some patients, or, occasionally,

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myoclonus in its own right. Sodium oxybate, the sodium salt form of gamma-hydroxybutyric acid, has been reported to decrease cortical myoclonus in a few patients. Deep brain stimulation One case of post-hypoxic myoclonus responded to chronic motor cortex stimulation. Evidence for a theoretical basis to stimulate subcortical sites does exist, most notable for the thalamus, but there is not a reported experience upon which to determine efficacy. 4.2. Cortical–subcortical myoclonus treatment The myoclonus in primary generalized epilepsies falls under this physiological classification [1]. Valproic acid is the major drug of choice for these disorders. The controlled evidence for efficacy is mostly for juvenile myoclonic epilepsy. Less impressive results are seen in other childhood myoclonic epilepsy syndromes. Lamotrigine may be used alone or used as an adjunct to valproic acid. The roles for ethosuximide, zonisamide, and clonazepam are mainly as adjuncts. 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. Intravenous valproic acid can be useful in myoclonic seizure status. 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. 4.3. Subcortical–suprasegmental myoclonus treatment Standard antiepileptic treatments are usually not helpful in subcortical myoclonus [1]. In essential myoclonus (including myoclonus–dystonia), treatments such as clonazepam and benzhexol (anti-cholinergic) can help but generally fail to match the amelioration seen with alcohol, and as a result there is a real danger of alcoholism in this condition. Sodium oxybate, the sodium salt form of gamma-hydroxybutyric acid, has been reported to decrease myoclonus in a few cases of myoclonus–dystonia. Deep brain stimulation of the thalamus or globus pallidus has had success in case reports and awaits confirmation in a larger number of patients. Reticular reflex myoclonus and opsoclonus–myoclonus respond partially to clonazepam. The opsoclonus–myoclonus syndrome has recently been reported to be responsive to intravenous immunoglobulin therapy, but it would appear that this may be treating the underlying autoimmune disorder rather than the myoclonus per se. In childhood, the opsoclonus–myoclonus syndrome may occur with a neuroblastoma, and treatment considerations differ from the adult form. Clonazepam is a useful treatment in hyperekplexia and sometimes in Propriospinal myoclonus.

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4.4. Segmental myoclonus treatment Palatal myoclonus is difficult to treat [1]. The list of drugs with anecdotal success in palatal myoclonus includes but is not limited to clonazepam, carbamazepine, lioresal, anticholinergics, tetrabenazine, valproic acid, phenytoin, lamotrigine, sumatriptan, and piracetam. Most commonly, palatal myoclonus fails these treatments. Because the ear clicking is so disabling when it occurs in palatal myoclonus, surgical treatments including tensor veli palatini tenotomy and occlusion of the Eustachian tube have been tried with variable success. Botulinum toxin injections have worked in some cases. Middle-ear myoclonus has been treated with tensor tympani and/or stapedius tenotomy as well as placement of ventilation tubes. Clonazepam, in dosages up to 6 mg daily, is the drug of first choice in spinal segmental myoclonus but usually leads to only partial improvement if there is an effect. Diazepam, carbamazepine, tetrabenazine, and levetiracetam have been useful in occasional cases. There are a few reports using botulinum toxin injections for the pain and movements of spinal segmental myoclonus with some success. 4.5. Peripheral myoclonus treatment For the quick movements in hemifacial spasm, botulinum toxin injections are known to work well [1]. Other causes of peripheral myoclonus have also responded to botulinum toxin injections. Drugs for peripheral myoclonus are usually unsatisfactory, but carbamazepine may have some effect.

5. Overall summary and conclusions Myoclonus continues to be studied and reported. However, much remains to be learned about this disabling disorder. The specific nature of the neuronal circuit abnormality responsible for the generation of myoclonus remains a mystery in any instance. For better treatments to be discovered, we must understand its physiology much better than we currently do. Such an understanding will require the use of different techniques working with a consistent myoclonus model. This must be are primary goal for the field of myoclonus.

Conflict of Interest statement None declared.

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