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Current thumbnail: Negative myoclonus is a motor disorder characterized by a sudden and abrupt interruption of muscular activity. The EMG correlate of negative myoclonus is a brief (< 500 msec) silent period, not preceded by any enhancement of EMG activity (ie, myoclonus). Negative myoclonus is an aspecific motor disorder that can be observed in a variety of physiological as well as pathological conditions. Epileptic negative myoclonus is defined as an interruption of tonic muscular activity, time-locked to a spike on the EEG, without evidence of an antecedent myoclonia. In this highlight, Carlo Alberto Tassinari, MD and Guido Rubboli, MD at the Department of Neurosciences, University of Bologna at Bellaria Hospital in Bologna (Italy), and Hiroshi Shibasaki MD at Human Motor Control Section, NINDS, NIH, in Bethesda, (USA), review the clinical features and the diagnostic procedures necessary to investigate negative myoclonus and provide an up-date on the latest advances in the understanding of the pathophysiological mechanisms underlying this motor disorder and report the most recent data on its pharmacological treatment.

Historical Note and Nomenclature
In 1949 Adams and Foley described, in patients suffering from hepatic encephalopathy, a disorder characterized by brief, involuntary jerky movements, when the patients were maintaining a posture (Adams and Foley 1949). To define this disorder, they coined the term asterixis. Electromyographic recordings showed that this phenomenon was due to short interruptions of the muscular activity. In the syndrome of post-hypoxic action myoclonus, Lance and Adams (Lance and Adams 1963) clearly documented a post-myoclonic period of muscular suppression: they noted also that, sometimes, a jerky movement related to “lapses of muscular contraction” could occur without evidence of a preceding myoclonus. Periods of "inhibition" of the muscular activity related to a spike were observed during "tonic" seizures by Tassinari and colleagues (Tassinari et al 1968). The involuntary short interruptions of the tonic contraction were labeled as "related epileptic silent period or R.E.S.P." Brief unilateral lapses of the postural tone, related to a contralateral focal spike on the EEG, were reported later on (Tassinari 1981). The term “negative myoclonus” was introduced by Shahani and Young in 1976; they analyzed the clinical and EMG characteristics of posthypoxic intention myoclonus and asterixis, and concluded that, "because these synchronous brief pauses, which occur at irregular intervals in the ongoing voluntary EMG activity, produce movements that appear clinically to be myoclonic, one may characterize this as ‘negative myoclonus’” (Shahani and Young 1976). Years later, the definition epileptic negative myoclonus was coined (Tassinari et al 1990; Guerrini et al 1993; Tassinari et al 1995) to identify an interruption of tonic muscular activity, time-locked to a spike on the EEG, without evidence of an antecedent myoclonus.|{diagram:NMCT1.bmp}{caption:Epileptic negative myoclonus in drug-resistant focal epilepsy}{label:Epileptic negative myoclonus in the right upper limp in a patient with drug-resistant focal epilepsy. Polygraphic recording showed the occurrence of spikes in the left central region associated with brief EMG interruptions on the right wrist extensor, ie, spikes associated with epileptic negative myoclonus (SaENM) (indicated by a black dot), and spikes unrelated to epileptic negative myoclonus (SuENM) (indicated by a black triangle). (Contributed by Carlo Alberto Tassinari MD FRCPC.)}||{diagram:NMCT2.bmp}{caption:Polygraphic recording in benign partial epilepsy and epileptic negative myoclonus}{label:Polygraphic recording in a child suffering from benign partial epilepsy and epileptic negative myoclonus in the right lower limb. Left panel: the EMG silent period of the epileptic negative myoclonus in the right lower limb is related to a spike-wave complex on the vertex with maximal amplitude on Cz. The onset of the EMG silent period follows the peak of the spike and precedes the onset of the slow wave. Right panel: the average of the spike-wave complexes associated with epileptic negative myoclonus, triggered from the peak of the spike, demonstrates the absence of any evidence of enhancement of the EMG activity preceding the onset of the epileptic negative myoclonus in the right tibialis anterior. Tib A: tibialis anterior; R: right; L: left; RTA: rectified EMG of the right tibialis anterior. (Contributed by Carlo Alberto Tassinari MD FRCPC.)}| Recently, the Task Force of the International League Against Epilepsy on Classification and Terminology has recognized “negative nyoclonus” as a seizure type (Engel 2001), defining it as an “interruption of tonic muscular activity for < 500 msec without evidence of preceding myoclonia” (Blume et al 2001).

Clinical Manifestations
Negative myoclonus appears as a shock-like involuntary jerky movement due to a sudden brief interruption of muscular activity. As proposed by Young and Shahani (Young and Shahani 1986), “asterixis” is a type of negative myoclonus; it can affect different muscles, such as orbicularis oculi, neck flexors, finger or wrist flexors and extensors, and hip extensors. This type of negative myoclonus (ie, asterixis) occurs typically in toxic-metabolic encephalopathies, often associated with reduced alertness; it can also be observed during the recovery phase following general anesthesia, with sedative drugs. Obeso and colleagues (Obeso et al 1995) considered, as a separate form of negative myoclonus , the postural lapses that can be observed in posthypoxic action myoclonus, characterized by interruptions of tonic muscular activity of postural muscles (neck, trunk, proximal leg muscles) lasting 200 to 500 msec, and usually following a myoclonic potential (Lance and Adams 1963). A similar phenomenon can be observed also in other diseases such as progressive myoclonus epilepsies (Lafora disease, Unverricht-Lundborg syndrome), torsion dystonia, cerebellar ataxia, and Huntington disease. In these conditions, a combination of positive myoclonus and negative myoclonus can often be observed; however, negative myoclonus seems to be the most disabling disturbance, significantly affecting the ability to stand or to walk.

In epileptic patients, epileptic negative myoclonus can be either unilateral or bilateral (Tassinari et al 1995). In some instances, this disorder can be clinically a mild, or almost undetected, motor event, giving rise to an "instability." More often, epileptic negative myoclonus can cause dropping of objects from the hands, “tremulousness” of a limb with difficulties in writing and feeding, head nodding, or, at times, gait instability and falls (Dalla Bernardina et al 1989; Colamaria et al 1991). Despite the relatively short duration, epileptic negative myoclonus can be so frequent as to lead to a severe motor disturbance resembling motor neglect of the affected arm. Capovilla and colleagues (Capovilla et al 2000) reported 2 children suffering from partial benign epilepsy and presenting with sudden falls and episodes of fecal incontinence, related to epileptic negative myoclonus in one lower limb and pelvic floor muscles. Indeed. polygraphic recordings showed EEG epileptic spikes located to the vertex associated with epileptic negative myoclonus in one lower limb|{diagram:NMCT2.bmp}{caption:Polygraphic recording in benign partial epilepsy and epileptic negative myoclonus}{label:Polygraphic recording in a child suffering from benign partial epilepsy and epileptic negative myoclonus in the right lower limb. Left panel: the EMG silent period of the epileptic negative myoclonus in the right lower limb is related to a spike-wave complex on the vertex with maximal amplitude on Cz. The onset of the EMG silent period follows the peak of the spike and precedes the onset of the slow wave. Right panel: the average of the spike-wave complexes associated with epileptic negative myoclonus, triggered from the peak of the spike, demonstrates the absence of any evidence of enhancement of the EMG activity preceding the onset of the epileptic negative myoclonus in the right tibialis anterior. Tib A: tibialis anterior; R: right; L: left; RTA: rectified EMG of the right tibialis anterior. (Contributed by Carlo Alberto Tassinari MD FRCPC.)}|, suggesting that epileptic spikes could cause a transitory dysfunction of the control of the lower limb muscles and the pelvic floor, whose cortical somatotopic representation lies in the fronto-mesial regions. Occurrence of epileptic negative myoclonus in neonatal age has been reported in association with other seizure types (spasms, atonic fits, generalized myoclonia) in a patient with Ohtahara syndrome and hemimegalencephaly (Guzzetta et al 2002).

Localization
Classifications based on the possible site of the generator have distinguished negative myoclonus in subcortical and cortical negative myoclonus (Obeso et al 1995; Shibasaki 1995; Tassinari et al 1998). Indeed, focal negative myoclonus has been reported in focal brain lesions involving subcortical structures such as thalamus, internal capsule and pons, and cortical structures such as the parietal lobe and the medial frontal cortex (Young and Shahani 1986; Palmer et al 1991).

Subcortical negative myoclonus is usually characterized by rhythmic, silent periods occurring usually at a rate of 6 to 11 Hz. No EEG correlates are detectable, even by using the technique of silent period-locked averaging. It may affect bilateral body segments (ie, both hands), although it may not be precisely synchronous. Early cortical components of somatosensory evoked potentials are not enhanced (Shibasaki 1995). Negative myoclonus observed in several types of toxic-metabolic encephalopathies (usually referred to as “asterixis”) presents the characteristics of subcortical negative myoclonus, although in some cases, the demonstration of a cortical correlate by means of averaging technique of the EMG-EEG signal (Ugawa et al 1989; Artieda et al 1992; Aguglia et al 1995) and the evidence of giant SEPs and a C-reflex (Toro et al 1995) supported a cortical origin.

The role of the primary somatosensory and motor cortices in the generation of negative myoclonus were investigated by means of single electrical pulse stimulations through subdural electrodes of the perirolandic areas (Ikeda et al 2000). A motor evoked potential followed by a silent period lasting up to 300 msec was observed in the contralateral hand muscles by stimulating some parts of the sensori-motor cortex. Duration of the silent period was proportional to the amplitude of the preceding motor evoked potential. Only occasionally, a pure silent period could be elicited stimulating the same cortical areas; in this case the length of the silent period depended on the intensity of the electrical shock. Additional data indicating the involvement of the primary motor cortex in the genesis of epileptic negative myoclonus have been provided by a recent magnetoencephalographic study in a child with atypical benign partial epilepsy (Kubota et al 2005).

Shibasaki (Shibasaki 2002) hypothesized that the generation of epileptic negative myoclonus requires an enhanced inhibitory activity in the primary motor cortex. Excessive inputs into the motor cortex, as it can occur following spontaneous epileptic activity in the premotor or postcentral areas, or due to enhanced excitability of the sensory cortex, can activate the inhibitory motor system, already hyperactive, suppressing the cortico-spinal volley to the spinal motoneurons, therefore, producing the EMG silent period that clinically results in negative myoclonus. The hypothesis of cortical inhibitory mechanisms mediating epileptic negative myoclonus was further supported by the inability of transcranial magnetic stimulation to elicit a motor evoked potentials when magnetic stimuli were delivered during the EMG silent period of epileptic negative myoclonus (Tassinari et al 1995). Preserved spinal excitability in epileptic negative myoclonus was demonstrated by recording normal F-waves during the period of muscular inhibition (Tassinari et al 1995). On the other hand, however, it is also possible that some negative myoclonus might be caused by excessive excitation of a group of cortical neurons which activate inhibitory interneurons at the spinal level.

Recently, the role of premotor cortex, primary somatosensory cortex and supplementary motor area in the generation of negative myoclonus was extensively investigated by means of single pulse intracerebral electrical stimulation through stereo-electroencephalographic electrodes (Rubboli et al 2004). Negative myoclonus could be observed by stimulating all these cortical areas, however, its occurrence by activation of premotor and primary somatosensory cortex depended on the intensity of stimulation, ie, negative myoclonus could be observed mainly at low stimulus intensity, whereas higher stimulation evoked a motor evoked potential followed by a silent period. On the contrary, supplementary motor area stimulation induced only negative myoclonus regardless of stimulus intensity.|{diagram:NMCT3.bmp}{caption:Stereo-EEG investigation for presurgical evaluation}{label:Intracerebral single pulse electrical stimulation of the right supplementary motor area in a drug-resistant epileptic patient undergoing stereo-EEG investigation for presurgical evaluation. Rectified EMG from the left deltoid; the arrow indicates the electrical stimulus. Superposition of two averages triggered from the electrical stimulus. At the highest intensity of stimulation, ie, 3 mA, the electric pulses induced a pure negative myoclonus, not preceded by any enhancement of the EMG activity. (Contributed by Carlo Alberto Tassinari MD FRCPC.)}|

Hypotheses suggesting that positive myoclonus and negative myoclonus are 2 distinct motor events (with positive myoclonus requiring the involvement of the primary motor cortex and negative myoclonus depending on the activation of cortical inhibitory areas), or 2 aspects of the same phenomenon (both resulting from an altered sensory-motor cortex output producing different degrees of positive or negative effects on the motor system) have been proposed (Toro et al 1995). It might be that both phenomena are associated more often than expected: indeed, negative myoclonus, to become apparent, requires a tonic contraction that could masquerade a preceding, or following, muscular burst; on the other hand, a myoclonic jerk at rest can be easily appreciated, whereas an associated silent period would not be observable, due to the lack of muscular tone.

Pathophysiology
In cortical negative myoclonus, EMG silent periods are usually longer in duration (100 to 400 msec) as compared to subcortical myoclonus. Cortical negative myoclonus of epileptic nature, ie, epileptic negative myoclonus is associated with an EEG event, such as an epileptic spike (Tassinari 1981; Guerrini et al 1993; Tassinari et al 1995), or a low amplitude EEG transient (Ugawa et al 1989). Tassinari and colleagues (Tassinari et al 1968; Tassinari 1981) showed that the onset of the EMG silent period was related to a negative component of the spike on the EEG, occurring before the slow-wave. The fact that negative myoclonus can be evoked by intracranial cortical stimulation with single electric pulses lends support to the hypothesis of a negative myoclonus related only to a spike event (Rubboli et al 2004).|{diagram:NMCT3.bmp}{caption:Stereo-EEG investigation for presurgical evaluation}{label:Intracerebral single pulse electrical stimulation of the right supplementary motor area in a drug-resistant epileptic patient undergoing stereo-EEG investigation for presurgical evaluation. Rectified EMG from the left deltoid; the arrow indicates the electrical stimulus. Superposition of two averages triggered from the electrical stimulus. At the highest intensity of stimulation, ie, 3 mA, the electric pulses induced a pure negative myoclonus, not preceded by any enhancement of the EMG activity. (Contributed by Carlo Alberto Tassinari MD FRCPC.)}| The involvement of cortical mechanisms has been clearly demonstrated in cortical reflex negative myoclonus, described by Shibasaki and colleagues (Shibasaki et al 1994) in progressive myoclonus epilepsies. In these patients, electrical stimulation of the median nerve, during sustained tonic contraction, caused a postural lapse at the wrists, with an EMG silent period ranging from 100 to 400 msec. A C-reflex could precede this stimulus-induced negative myoclonus. Occurrence of induced EMG silent period and giant SEPs were significantly correlated. Furthermore, recovery function of the N33 component was slow and similar to the duration of the induced EMG silent period. Summarizing these evidences, the authors concluded that this form of stimulus-induced negative myoclonus occurred via a transcortical reflex mechanism, hence the definition of "cortical reflex negative myoclonus."

A frontal EEG potential encompassed in spikes associated with epileptic negative myoclonus, preceding the onset of the interruption of the tonic muscular activity by about 30 msec, has been described by Rubboli and colleagues (Rubboli et al 1995).|{diagram:NMCT4.bmp}{caption:Spike averages in epileptic negative myoclonus}{label:Upper panel: on the left, spike average of the spikes associated with epileptic negative myoclonus (SaENM); epileptic negative myoclonus in the rectified EMG is indicated by the arrow. On the right, spike average of the spikes unrelated to epileptic negative myoclonus (SuENM). In SaENM, the onset the EMG silent period of epileptic negative myoclonus precedes the slow-wave that follows the spike. Lower panel: superposition of the averages of SaENM and SuENM at F3, C3, P3. SaENM (thicker tracing) differs from SuENM for a second spike component mainly distributed on F3, suggesting that epileptic negative myoclonus in the right upper limb occurs when epileptic activity spreads to the left frontal areas. (Modified from Rubboli et al 1995)}| Baumgartner and colleagues (Baumgartner et al 1996), by combined use of EEG and SPECT-MRI coregistration, and Meletti and colleagues (Meletti et al 2000) provided further evidences supporting a role of frontal cortical regions in the generation of epileptic negative myoclonus. These findings may be supported by the results of intracerebral electrical stimulation in epileptic patients that demonstrated the existence, in the lateral and mesial aspects of the frontal lobes, of cortical areas whose activation can produce motor inhibition (Luders et al 1987; Lim et al 1994). The involvement of post-central parietal areas has been suggested by Noachtar and colleagues (Noachtar et al 1997) who showed the association of epileptic spikes in the postcentral cortex recorded by subdural grids associated with epileptic negative myoclonus in the contralateral upper limb.

Differential Diagnosis
The clinical features of negative myoclonus, ie, a sudden involuntary jerk, sometimes may render difficult its distinction from positive myoclonus. In addition, in certain conditions both disorders are commonly observed in the same patient.|{diagram:NMCT5.bmp}{caption:Polygraphic recording showing occurrence of both positive and negative myoclonus}{label:Polygraphic recording in a patient with progressive myoclonus epilepsy showing the occurrence of both positive myoclonus and negative myoclonus. (Modified from Tassinari et al 1995.)}| It must be pointed out that to unveil negative myoclonus a tonic contraction of the affected muscle is necessary, and that the diagnosis of negative myoclonus requires the exclusion of a positive myoclonus preceding the onset of the EMG silent period.

Negative myoclonus can occur in a continuous fashion, rhythmic or arrhythmic, as soon as the patient maintains a posture: in this case, the affected limbs look “tremulous,” and, depending also on the frequency of this “tremulousness,” it might require differentiation from tremor. Indeed, in negative myoclonus, polygraphic recording demonstrates the simultaneous interruption of EMG activity in agonist and antagonist muscles, whereas in tremor, the muscular contractions in the two muscular groups tend to occur in an alternate fashion.

In epileptic patients, sudden postural lapses leading to a fall to the ground may be caused by epileptic negative myoclonus involving axial and leg musculature (Rubboli et al 1997; Capovilla et al 2000; Shibasaki 2002).

Diagnostic Workup
Incidence and prevalence of epileptic negative myoclonus are underestimated, due to the fact that this disorder must be looked for, and that it can be mild and transitory. Polygraphic recording is the essential neurophysiological tool to define epileptic negative myoclonus. Indeed, only simultaneous EEG-EMG monitoring, recording activity from agonist and antagonist muscles of the body segment affected by epileptic negative myoclonus, can allow the diagnosis of this motor disturbance, by showing a brief interruption of a tonic EMG activity not preceded by a positive myoclonus.|{diagram:NMCT1.bmp}{caption:Epileptic negative myoclonus in drug-resistant focal epilepsy}{label:Epileptic negative myoclonus in the right upper limp in a patient with drug-resistant focal epilepsy. Polygraphic recording showed the occurrence of spikes in the left central region associated with brief EMG interruptions on the right wrist extensor, ie, spikes associated with epileptic negative myoclonus (SaENM) (indicated by a black dot), and spikes unrelated to epileptic negative myoclonus (SuENM) (indicated by a black triangle). (Contributed by Carlo Alberto Tassinari MD FRCPC.)}||{diagram:NMCT2.bmp}{caption:Polygraphic recording in benign partial epilepsy and epileptic negative myoclonus}{label:Polygraphic recording in a child suffering from benign partial epilepsy and epileptic negative myoclonus in the right lower limb. Left panel: the EMG silent period of the epileptic negative myoclonus in the right lower limb is related to a spike-wave complex on the vertex with maximal amplitude on Cz. The onset of the EMG silent period follows the peak of the spike and precedes the onset of the slow wave. Right panel: the average of the spike-wave complexes associated with epileptic negative myoclonus, triggered from the peak of the spike, demonstrates the absence of any evidence of enhancement of the EMG activity preceding the onset of the epileptic negative myoclonus in the right tibialis anterior. Tib A: tibialis anterior; R: right; L: left; RTA: rectified EMG of the right tibialis anterior. (Contributed by Carlo Alberto Tassinari MD FRCPC.)}| Multiple EMG recordings from different limb and axial muscles can show the distribution pattern of negative myoclonus in different body segments. To be diagnosed, negative myoclonus must be looked for by asking the patient to maintain a tonic contraction in the body segment affected by this motor disorder. The association of an EEG spike time-locked to negative myoclonus leads to the diagnosis of epileptic negative myoclonus. In some instances, visual inspection of the polygraphic tracing fails to detect any EEG abnormality associated with negative myoclonus. The application of computerized averaging technique such as back-averaging, silent period locked averaging or spike averaging (Ugawa et al 1989; Rubboli et al 1995, Tassinari et al 1995) can be effective in the extraction of a cortical potential associated with epileptic negative myoclonus from the background EEG activity, and to better define the temporal relationships between the EEG and the EMG events. In addition, back-average of the EMG signal triggered from the associated EEG spike or from the onset of the EMG silent period is helpful to demonstrate the absence of possible myoclonic bursts preceding the EMG silent period of epileptic negative myoclonus.|{diagram:NMCT2.bmp}{caption:Polygraphic recording in benign partial epilepsy and epileptic negative myoclonus}{label:Polygraphic recording in a child suffering from benign partial epilepsy and epileptic negative myoclonus in the right lower limb. Left panel: the EMG silent period of the epileptic negative myoclonus in the right lower limb is related to a spike-wave complex on the vertex with maximal amplitude on Cz. The onset of the EMG silent period follows the peak of the spike and precedes the onset of the slow wave. Right panel: the average of the spike-wave complexes associated with epileptic negative myoclonus, triggered from the peak of the spike, demonstrates the absence of any evidence of enhancement of the EMG activity preceding the onset of the epileptic negative myoclonus in the right tibialis anterior. Tib A: tibialis anterior; R: right; L: left; RTA: rectified EMG of the right tibialis anterior. (Contributed by Carlo Alberto Tassinari MD FRCPC.)}||{diagram:NMCT4.bmp}{caption:Spike averages in epileptic negative myoclonus}{label:Upper panel: on the left, spike average of the spikes associated with epileptic negative myoclonus (SaENM); epileptic negative myoclonus in the rectified EMG is indicated by the arrow. On the right, spike average of the spikes unrelated to epileptic negative myoclonus (SuENM). In SaENM, the onset the EMG silent period of epileptic negative myoclonus precedes the slow-wave that follows the spike. Lower panel: superposition of the averages of SaENM and SuENM at F3, C3, P3. SaENM (thicker tracing) differs from SuENM for a second spike component mainly distributed on F3, suggesting that epileptic negative myoclonus in the right upper limb occurs when epileptic activity spreads to the left frontal areas. (Modified from Rubboli et al 1995)}| Recently, magnetoencephalography has been used to investigate the cortical sources of epileptic activity associated with epileptic negative myoclonus in a patient with atypical benign partial epilepsy (Kubota et al 2005).

Extensive neurophysiological investigations can allow the study of the excitability of the sensory and motor cortices, providing complementary information regarding the pathophysiology of negative myoclonus (Tassinari et al 1998; Shibasaki 2000). Evoked potentials associated with study of the long loop reflexes are relevant to investigate cortical sensitivity to various stimuli, ie, reflex myoclonus, and possibly the recovery functions of the cortical response and reflex negative myoclonus (Shibasaki et al 1994; Shibasaki 2000). Transcranial magnetic stimulation and F-wave assessment have been used to evaluate motor system excitability at a cortical and spinal level, respectively, during EMG silent period of epileptic negative myoclonus (Tassinari et al 1995).

Neuroimaging techniques, in particular MRI, can be useful to detect brain abnormalities and to investigate their relationships with the topography of the epileptic negative myoclonus related-EEG activity. Malformations of cortical development have been reported to be associated with focal epileptic negative myoclonus (Colamaria et al 1989; Guerrini et al 1993; Dalla Bernardina et al 1995; Tassinari et al 1995; Noachtar et al 1997; Guzzetta et al 2002; Caraballo et al 2004). Functional neuroimaging with EEG-SPECT co-registration in a patient with epileptic negative myoclonus has been used to investigate the cortical areas involved in the generation of this motor disorder, suggesting a role of the premotor cortex (Baumgartner et al 1996).

Syndromes and Diseases in which Seizure Type Occurs
Epileptic negative myoclonus is an unspecific motor disorder that can be observed in a wide variety of epileptic conditions, classified, according to etiological criteria, as idiopathic, symptomatic, and cryptogenic (Tassinari et al 1995). In the idiopathic group, it is usually detected in children suffering from partial epilepsy of infancy (including benign epilepsy with rolandic spikes) (Dalla Bernardina et al 1989; Kanazawa and Kawai 1990; Oguni et al 1992; 1998; Tassinari et al 1995; Capovilla et al 1999; 2000). Epileptic negative myoclonus as isolated clinical manifestations has never been reported; seizures associated with epileptic negative myoclonus can be partial motor (often of the rolandic type), absences, or atonic. The evolution of both epileptic negative myoclonus and epilepsy in this group of patients is usually benign. In the pediatric age, epileptic negative myoclonus can be observed in the “epileptic encephalopathy with electrical status epilepticus during sleep” or “ESES syndrome.” In this condition, epileptic negative myoclonus is associated with various seizure types and impairment of higher functions, such as language regression, behavioral disturbances and ataxia (Tassinari et al 2002). Gambardella and colleagues (Gambardella et al 1996) described a patient with photic-induced negative myoclonus suffering from a form of idiopathic generalized epilepsy.

Epileptic negative myoclonus can occur in pediatric as well as adult patients in symptomatic epileptic conditions such as mitochondrial diseases, birth anoxia, vascular malformations, progressive myoclonus epilepsies, epileptic encephalopathies, and neuronal migration disorders; for a review, see (Werhahn and Noachtar 2000; Nabbout and Dulac 2003). Seizure types associated with epileptic negative myoclonus in these epileptic conditions can vary from simple to complex partial seizures, tonic seizures, spasms, and generalized tonic-clonic seizures. Occurrence of epileptic negative myoclonus in a newborn with Ohtahara syndrome and hemimegalencephaly has been recently reported (Guzzetta et al 2002).

It is important to keep in mind that negative myoclonus is not infrequently induced as the side effects of various anticonvulsive drugs as described later in this chapter.

Prognosis and complications
Evolution and prognosis of negative myoclonus are mainly related to etiology. In patients with idiopathic epilepsy and epileptic negative myoclonus, the motor disorder is usually transitory, it may last 1 to 2 years, and the prognosis of both epilepsy and epileptic negative myoclonus are usually favorable. In addition, during the period in which epileptic negative myoclonus is present, it can be often controlled by appropriate drug therapy. In patients with epileptic negative myoclonus associated with symptomatic epilepsy, the evolution and prognosis of both epilepsy and epileptic negative myoclonus is related to underlying etiological factors and to the specific syndromic picture. Indeed, in patients suffering from conditions such as progressive myoclonus epilepsies and symptomatic drug-resistant focal epilepsies associated with malformations of cortical development, epileptic negative myoclonus can be a long-lasting and disabling disturbance.

Management
Several data have demonstrated the effectiveness of ethosuximide in the treatment of epileptic negative myoclonus in children suffering from idiopathic partial epilepsy (Oguni et al 1998; Capovilla et al 1999; 2000; Shirasaka and Mitsuyoshi 1999; Kubota et al 2005). These evidences have suggested that this drug, specifically acting as T-type Ca2+ blocker on thalamic neurons and related cortical assemblies, may modulate at the thalamo-cortical level the physiopathogenic mechanisms possibly involved in the genesis of epileptic negative myoclonus. Another drug that has been recently reported to control epileptic negative myoclonus is levetiracetam, however, more extensive studies are needed to confirm these preliminary findings (Gelisse et al 2003). Epileptic negative myoclonus associated with symptomatic or cryptogenic epilepsies is usually less responsive to common antiepileptic treatments.

Several data have demonstrated the induction or worsening of epileptic negative myoclonus by carbamazepine in children suffering from partial epilepsies (Caraballo et al 1989; Nanba e Maegaki 1999; Shirasaka and Mitsuyoshi 1999; Parmeggiani et al 2004). Other drugs that have been reported to be able to induce epileptic negative myoclonus are valproic acid (Aguglia et al 1995), phenytoin (Young and Shahani 1986; Chi et al 2000), lamotrigine (Cerminara et al 2004), and oxcarbazepine (Hahn et al 2004).

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Synonyms
Epileptic negative myoclonus

Subtopics
Asterixis

Major Keyword Descriptors
asterixis
finger flexors
neck flexors
orbicularis oculi
tonic contraction
tonic muscular activity
toxi-metabolic encephalopathies
wrist flexors

Minor Keyword Descriptors
epilepsy
myoclonus
posture
seizure

Age of Presentation
0-01 month
01-23 months
02-05 years
06-12 years
13-18 years
19-44 years
45-64 years
65+ years

Age of Typical Presentation
0-01 month
01-23 months
02-05 years
06-12 years
13-18 years
19-44 years
45-64 years
65+ years

Figure legends
Fig. 1. Epileptic negative myoclonus in the right upper limb in a patient with drug-resistant focal epilepsy. Polygraphic recording showed the occurrence of spikes in the left central region associated with brief EMG interruptions on the right wrist extensor, ie, spikes associated with epileptic negative myoclonus (SaENM) (indicated by a black dot), and spikes unrelated to epileptic negative myoclonus (SuENM) (indicated by a black triangle).

Fig. 2. Polygraphic recording in a child suffering from benign partial epilepsy and epileptic negative myoclonus in the right lower limb. Left panel: the EMG silent period of the epileptic negative myoclonus in the right lower limb is related to a spike-wave complex on the vertex with maximal amplitude on Cz. The onset of the EMG silent period follows the peak of the spike and precedes the onset of the slow wave. Right panel: the average of the spike-wave complexes associated with epileptic negative myoclonus, triggered from the peak of the spike, demonstrates the absence of any evidence of enhancement of the EMG activity preceding the onset of the epileptic negative myoclonus in the right tibialis anterior.

Tib. A: tibialis anterior; R: right; L: left; RTA: rectified EMG of the right tibialis anterior.

Fig. 3. Intracerebral single pulse electrical stimulation of the right supplementary motor area in a drug-resistant epileptic patient undergoing stereo-EEG investigation for presurgical evaluation. Rectified EMG from the left deltoid; the arrow indicates the electrical stimulus. Superposition of two averages triggered from the electrical stimulus. At the highest intensity of stimulation, ie, 3 mA, the electric pulses induced a pure negative myoclonus, not preceded by any enhancement of the EMG activity.

Fig. 4. Upper panel: on the left, spike average of the spikes associated with epileptic negative myoclonus (SaENM); epileptic negative myoclonus in the rectified EMG is indicated by the arrow. On the right, spike average of the spikes unrelated to epileptic negative myoclonus (SuENM). In SaENM, the onset the EMG silent period of epileptic negative myoclonus precedes the slow-wave that follows the spike. Lower panel: superposition of the averages of SaENM and SuENM at F3, C3, P3. SaENM (thicker tracing) differs from SuENM for a second spike component mainly distributed on F3, suggesting that epileptic negative myoclonus in the right upper limb occurs when epileptic activity spreads to the left frontal areas. (Modified from Rubboli et al 1995)

Fig. 5. Polygraphic recording in a patient with progressive myoclonus epilepsy showing the occurrence of both positive myoclonus and negative myoclonus. (Modified from Tassinari et al 1995)

Permutations
Negative myoclonus
myoclonus, Negative
negative myoclonus, Epileptic
myoclonus, Epileptic negative

Related Topics
Atonic seizures
Epilepsia partialis continua
Gait disorders
Myoclonic status
Myoclonic-atonic seizures
Myoclonus

Differential Diagnosis
positive myoclonus
tremor

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