Myoclonus and epilepsy

Handbook of Clinical Neurology, Vol. 111 (3rd series) Pediatric Neurology Part I O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 69

Myoclonus and epilepsy RENZO GUERRINI1* AND TAKEO TAKAHASHI2 Pediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer — University of Florence, Florence, Italy

1

2

Department of Paediatrics (Neurology), Keio University School of Medicine, Tokyo, Japan

INTRODUCTION The term “myoclonus” is used to describe a brief and jerky involuntary movement, originating from brief active contractions of muscles (positive myoclonus) or, more rarely, from brief interruptions of ongoing electromyographic activity (negative myoclonus) (Marsden et al., 1982). Clinically, myoclonus may be classified as “focal”, “multifocal,” or “generalized”. It may be spontaneous or induced by movement (action myoclonus), or by sensory or visual stimuli (reflex myoclonus). Finally, as regards periodicity, myoclonus may be rhythmic or arrhythmic. Four major clinical categories are identified in the etiological classifications of myoclonus (Marsden et al., 1982; Fahn et al., 1986): (a) physiological myoclonus (sleep-related, hiccup, myoclonus induced by anxiety or exercise); (b) essential myoclonus (individuals without other neurological signs); (c) epileptic myoclonus (conditions in which the predominant element is epilepsy); and (d) symptomatic myoclonus (conditions in which the predominant element is encephalopathy). Neurophysiological characteristics, on the other hand, divide myoclonus into six main categories: cortical, cortical-subcortical, subcortical-supraspinal, spinal, and peripheral (Caviness and Brown, 2006). The definition of “epileptic myoclonus” has been noncommittal. Some authors define as “epileptic myoclonus” the one that occurs within the setting of epilepsy (Patel and Jankovic, 1988). Others define as epileptic myoclonus those forms in which a paroxysmal depolarization shift is supposed to be the underlying neurophysiological substrate, irrespective of what neuronal population (cortical or subcortical) is primarily involved (Hallett, 1985). In our opinion, epileptic myoclonus can be comprehensively defined as an elementary electroclinical manifestation

of epilepsy involving descending neurons, whose spatial (spread) or temporal (self-sustained repetition) amplification can trigger overt epileptic activity (Guerrini et al., 2002a). Often, the EEG correlate of epileptic myoclonus can be detected only by using jerk-locked (EEG or magnetoencephalogram) averaging. Yet, many patients with cortical myoclonus have rhythmic EMG bursts at relatively high frequency (especially those with minipolymyoclonus, cortical tremor, Angelman syndrome or autosomal dominant cortical myoclonus and epilepsy), which make it difficult to identify a cortical correlate. Recent work has demonstrated in these cases the role of EEG–EMG coherence by means of frequency analysis in demonstrating common cortical drives (Brown et al., 1999; Grosse et al., 2003; Van Rootselaar et al., 2006). Myoclonus can be either one of multiple components of a seizure (myoclonic jerks heralding a generalized tonic–clonic seizure in juvenile myoclonic epilepsy or in progressive myoclonus epilepsies), the sole ictal manifestation (myoclonic jerks of benign myoclonic epilepsy), one of multiple seizure types (as observed in myoclonic–astatic epilepsy), or the basis of a movement related disorder (action myoclonus in progressive myoclonus epilepsies). The relationships between myoclonus and epilepsy have been elucidated in part whereas the neurophysiological bases, nosology, and electroclinical characteristics of myoclonus in the setting of specific epilepsy syndromes are to be further investigated. Recent evidence has indicated that epileptic myoclonus can be classified neurophysiologically as cortical (positive and negative), secondarily generalized, thalamo-cortical, and reticular reflex myoclonus (Guerrini et al., 2005a). Cortical epileptic myoclonus constitutes a fragment of

*Correspondence to: Renzo Guerrini, M.D., Pediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer – University of Florence, Viale Pieraccini 24, 50139 Firenze, Italy. Tel: 390555662573, Fax: 390555662329, E-mail: [email protected]

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partial or symptomatic generalized epilepsy; thalamocortical epileptic myoclonus is a fragment of idiopathic generalized epilepsy (Hallett, 1985). Reflex reticular myoclonus, which does not have a time-locked EEG correlate, represents the clinical counterpart of hypersynchronous activity of neurons in the brainstem reticular formation. In the following sections major epilepsy or neurological syndromes featuring different forms of epileptic myoclonus are described.

CORTICAL MYOCLONUS Cortical myoclonus (CM) stems from abnormal neuronal discharges in the sensorimotor cortex. Abnormally firing motoneurons may be hyperexcitable themselves or may be driven by abnormal inputs from hyperexcitable parietal (Deuschl et al., 1991) or occipital (Kanouchi et al., 1997) areas. Each jerk corresponds to a discharge of a small group of cortical motoneurons, somatotopically connected to a group of contiguous muscles. A cortical potential, time-locked to the myoclonic potential, and localized on the contralateral sensorimotor region, may be demonstrated by EEG, magnetoencephalogram, or jerk-locked averaging (Shibasaki and Kuroiwa, 1975; Hallett et al., 1979; Shibasaki et al., 1991; Mima et al., 1998). Facilitation of interhemispheric and intrahemispheric spread of CM activity through transcallosal or cortico-cortical pathways seems to play a major role in producing generalized or bilateral myoclonus (Brown et al., 1991a). In patients with cortical reflex myoclonus (CRM), appropriate stimuli administered to a resting somatic segment produce a reflex muscle response (jerk) with a latency of around 50 ms (C-reflex) (Sutton and Mayer, 1974). A similar response is only observed in normal subjects during voluntary contraction. Somatosensory evoked potentials (SEPs) of giant amplitude are typically seen in association with CRM (Shibasaki et al., 1985; Rothwell et al., 1986; Ikeda et al., 1995; Hitomi et al., 2006). The striking resemblance in latency and morphology of the giant SEPs to the myoclonus related cortical spikes suggests that both originate from common cortical mechanisms (Shibasaki et al., 1991). In the typical forms of CRM, the reflex jerk in the hand has a latency of
50 ms with a mean duration of 7 ms (Thompson et al., 1994b). Typical CRM can be observed in patients with focal cortical lesions (Sutton and Mayer, 1974), spinocerebellar degeneration (Hallett et al., 1979), multiple system atrophy, cerebral anoxia (Hallett et al., 1979), childhood metabolic degenerations such as neuronal ceroid lipofuscinosis and sialidosis (Shibasaki et al., 1985; Deuschl et al., 1991), Alzheimer’s disease, Down syndrome, and mitochondrial disorders.

Epileptic negative myoclonus (ENM) is characterized by brief (50–400 ms) muscle inhibitions with focal, multifocal, or bilateral distribution and time-locked to sharp wave or spike-wave discharges on the contralateral central areas (Guerrini et al., 1993; Shibasaki, 1995). Epileptic negative myoclonus has a wide etiological spectrum ranging from idiopathic to symptomatic forms due to cortical dysplastic lesions (Guerrini et al., 2002a). It may occasionally be precipitated by an adverse reaction to antiepileptic drugs (Guerrini et al., 1998a; Cerminara et al., 2004; Parmeggiani et al., 2004). Previous studies (Shibasaki, 1995; Noachtar et al., 1997; Ikeda et al., 2000) hypothesized a cortical origin of ENM. Epileptic activity associated with ENM was described in the premotor (Rubboli et al., 1995; Baumgartner et al., 1996; Meletti et al., 2000) and postcentral somatosensory cortex (Tassinari et al., 1995b; Noachtar et al., 1997). Through cortical electrical stimulation studies it was suggested that negative motor areas might be present in the lateral and mesial portion of frontal lobe, encompassed in the SMA (L€ uders et al., 1995). A possible role of the SMA in ENM was also proposed in a recent study (Rubboli et al., 2006) in which electrical stimulation of the SMA constantly evoked ENM, with no preceding positive myoclonus, as it was instead observed following stimulation of the premotor, primary motor, and sensorimotor cortex.

Epileptic syndromes and neurological disorders with CM CORTICAL ACTION/REFLEX MYOCLONUS Progressive myoclonus epilepsies Progressive myoclonus epilepsies (PMEs) represent a clinically and etiologically heterogeneous group of diseases with progessive course, characterized by myoclonus, generalized tonic–clonic seizures, and neurological deterioration (Commission, 1989). Onset is most frequently in late childhood or adolescence (Genton et al., 2005). Different forms are known, including Unverricht–Lundborg disease, Lafora disease (Fig. 69.1), neuronal ceroid lipofuscinosis, type III Gaucher disease, infantile and juvenile GM2-gangliosidosis, some mitochondrial encephalopathies, sialidosis, dentatorubro-pallidoluysian atrophy, and action myoclonus-renal failure (AMRF) (Badhwar et al., 2004; Genton et al., 2005). Causative genes have been identified for most PMEs (Delgado-Escueta et al., 2001; Guerrini et al., 2006). Onset features comprise myoclonus and rare generalized tonic–clonic seizures, as in idiopathic myoclonic epilepsies (Roger et al., 1992). The tonic–clonic seizures can occur without any warning or after a long build up of myoclonic jerks. The EEG shows generalized polyspike and spike-and-wave discharges,

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Fig. 69.1. A 16-year-old girl with Lafora disease. Polygraphic EEG recording. On the left: the girl is awake. The EEG shows mild slowing of background activity with superimposed generalized and multifocal discharges of spikes, polyspikes, and spikes and waves. One generalized discharge is accompanied by a small series of myoclonic jerks, which are visible on the recorded EMG channels and appear to be synchronous with the EEG spikes. On the right: EEG recording while asleep. There are abundant slow waves, no sleep spindles are recognizable, and generalized and focal EEG discharges persist.

often precipitated by photic stimulation. Background EEG activity becomes progressively slower (Roger et al., 1992). Cortical reflex myoclonus is common to all PME syndromes, in which it is manifested with the classic combination of action myoclonus, spontaneous jerks, giant SEPs, C-reflex at rest, and the premyoclonus spike. According to Cantello et al. (Cantello et al., 1997), focal subcortical reflex myoclonus can also be demonstrated in these patients. Initially mild, myoclonus becomes increasingly disabling during the course. Severe action myoclonus has a devastating impact on the patients’ level of autonomy. Rett syndrome Rett syndrome is an X-linked dominant disorder, with an estimated prevalence of 1 in 10 000–15 000 females making it one of the most common causes of severe mental retardation in females. Mutations in exons 1–4 of the methyl CpG binding protein 2 gene (MECP2) (Amir et al., 1999) have been identified in roughly 75–80% of girls with classical Rett syndrome (Auranen et al., 2001); in MECP2-negative patients additional screening using MLPA (Multiplex Ligation Probe Amplification) enables to detect large deletions in nearly half of the remaining patients with the syndrome (Scala et al., 2007). Rare males have been reported with a severe early onset and progressive encephalopathy due to MECP2 mutations, also exhibiting cortical myoclonus (Leuzzi et al., 2004). The clinical phenotype in classical Rett syndrome in females includes progressive cognitive deterioration leading to dementia, autistic features,

truncal ataxia/apraxia, loss of purposeful hand movements, breathing abnormalities, stereotypies, extrapyramidal signs, and epilepsy. A form of CRM characterized by prolonged C-reflex (65 þ 5 ms) latency has been described in affected girls (Guerrini et al., 1998b). Myoclonus is multifocal and arrhythmic and major myoclonic seizures are not seen in these patients. A positive potential, localized on the contralateral centro-parietal area, precedes myoclonus with a latency of 34 þ/ 7 ms for the forearm muscle compatible with corticomotoneuronal conduction. The N20-P30 and P30-N35 components of the SEPs have significantly increased amplitude. In addition, the latency of the N20 component is delayed, and the N20-P30-N35 interval is significantly increased and has expanded morphology. It is probable that in Rett syndrome the following sequence of events occurs: slight delay in central conduction of the impulse afferent to the sensorimotor cortex (N20), slowing of the processing of the afferent impulse (interval N20–P30; mean ¼ 11 ms), delay in cortico-cortical transmission to the pre-central neurons subserving movement of the stimulated body segment (latency increase P30 – C-reflex; mean ¼ 32 ms), and rapid descending volley to the spinal motoneurons. Intra-cortical conduction time could be particularly prolonged on account of the synaptic abnormalities, which have been observed (Armstrong, 2002). Huntington’s disease In Huntington’s disease action myoclonus is a rare manifestation, but a few patients have been described in

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whom CRM was the presenting symptom (Carella et al., 1993; Thompson et al., 1994a). Seizures are an infrequent complication and are mainly seen with juvenile onset, rarely presenting with a typical PME syndrome (Gambardella et al., 2001). Postanoxic encephalopathy Postanoxic encephalopathy is characterized by dysarthria, ataxia, pyramidal signs, rigidity, epilepsy, and myoclonus, which is usually spontaneous and actioninduced, multifocal and generalized, and extremely disabling. Electromyographic silent periods following the jerks contribute to producing postural lapses (Lance and Adams, 1963). Postanoxic myoclonus may be cortical in origin, involving the sensorimotor cortex and rapidly conducting pyramidal pathways (Hallett et al., 1979; Young and Shahani, 1979). More rarely it may have brainstem origin, either as exaggerated startle reflex or as reticular reflex myoclonus (Hallett et al., 1977; Brown et al., 1991b). Forty percent of patients with postanoxic myoclonus suffer from generalized epileptic seizures.

FOCAL CORTICAL REPETITIVE MYOCLONUS Epilepsia partialis continua Epilepsia partialis continua or “Kojewnikow’s syndrome” (Kojewnikow, 1895), is characterized by almost continuous focal, rhythmic (around 1–2 Hz) muscle jerks, which are observed both while awake and asleep, for periods ranging from hours to days, or rarely years (Commission, 1989). Unilateral somatomotor seizures are constantly associated. Two types of epilepsia partialis continua have been identified (Bancaud, 1992). The first type is due to fixed epileptogenic lesions involving the motor cortex. Causative factors include ischemia, posttraumatic head injury, cortical dysplasia, tumors, and vascular malformations (Thomas et al., 1977; Bancaud, 1992; Fusco et al., 1992; Kuzniecky and Powers, 1993). A stable motor deficit, predating seizure onset, and nonprogressive evolution are usual features. A second type of epilepsia partialis continua is observed in Rasmussen’s syndrome. Onset occurs during childhood, with continuous focal jerking and intractable homolateral motor or generalized seizures. Progressive hemiparesis, hemianopia, and, eventually, cognitive deterioration follow. MRI shows progressive atrophy of the affected hemisphere. Pathological studies reveal inflammation with perivascular infiltrates and microglia nodules (Andrews et al., 1997). A viral etiology was originally hypothesized. A role of antibody-mediated mechanisms and more recently cell-mediated immunity has been hypothesized (Rogers et al., 1994; Hart, 2004;

Watson et al., 2004) with inconclusive results. An analogous form of progressive epilepsia partialis continua has been observed in some children with MELAS (Veggiotti et al., 1995).

RHYTHMIC HIGH-FREQUENCY CORTICAL MYOCLONUS (CORTICAL TREMOR) Cortical tremor is a form of rhythmic myoclonus, presenting as postural or action tremor in some patients with progressive myoclonus epilepsy (PMEs) (Ikeda et al., 1990; Toro et al., 1993), in Angelman syndrome, and in different forms of autosomal dominant epilepsy (Terada et al., 1997; Guerrini et al., 2001; Gardella et al., 2006; Carr et al., 2007). The nosologic boundaries between epilepsia partialis continua and this peculiar form of repetitive myoclonus are unclear (Guerrini, 2009). Angelman syndrome Angelman syndrome (Fig. 69.2) is caused by a defect in maternal chromosome 15q11-q13. Seventy percent of patients present a cytogenetic or molecular deletion encompassing three subunits of receptor a for gammaaminobutyric acid (GABRB3, GABRA5, and GABRG3) and the gene UBE3A. Uniparental paternal disomy for chromosome 15, or mutations in the imprinting center or in the UBE3A gene are more rarely found. Patients have microbrachicephaly, severe to moderate mental retardation, absence of speech, inappropriate paroxysmal laughter, epilepsy, ataxic gait, tremor, and jerky movements. Neurophysiological investigations reveal a spectrum of manifestations of myoclonus (Guerrini et al., 1996). All patients present with prolonged runs of rapid distal jerking of fluctuating amplitude, which causes a sort of coarse distal tremor combined with dystonic limb posturing. Most patients exhibit myoclonic and absence seizures, as well as episodes of myoclonic status. Bilateral jerks of myoclonic absences show rhythmic repetition at
2.5 Hz and are time-locked with a cortical spike. Interside latency of both spikes and jerks is consistent with transcallosal spread and spike-to-jerk latency indicates propagation through rapid conduction cortico-spinal pathway. A contralateral, central premyoclonic potential is uncovered by jerk-locked averaging. SEPs are normal and C-reflex is absent. Familial adult myoclonic epilepsy and autosomal dominant cortical reflex myoclonus and epilepsy A form of autosomal dominant epilepsy with cortical myoclonic tremor has been described in several families, mostly of Japanese origin and given the acronym of BFAME (benign familial adult myoclonic epilepsy) or FAME (familial adult myoclonic epilepsy). Affected

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Fp2 F4 C4 P4 L. Delt L. Ext L. Flex Fp1 F3 C3 P3 R. Delt R. Ext R. Flex Fz Cz 1 sec 100 mV

Fig. 69.2. A 15-year-old girl with Angelman syndrome. A run of rhythmic myoclonic jerks at around 12–15 Hz is recorded from the wrist extensor and flexor muscles and deltoid muscles bilaterally. A rhythmic EEG activity at 7 Hz is simultaneously recorded. Distal, high-freqency myoclonus is interrupted by rhythmic generalized jerks at 2 Hz, which are time locked to the spike components of a generalized spike-and-wave discharge. This image provides an example of two types of epileptic myoclonus in Angelman syndrome.

patients present homogeneous characteristics including: (a) autosomal dominant inheritance; (b) adult onset (mean age 38 years, range: 19–73); (c) an initially progressive then stable course; (d) distal, rhythmic myoclonus enhanced during posture maintenance; (e) rare, apparently generalized seizures often preceded by worsening of myoclonus; (f) absence of other neurological signs; (g) generalized interictal spike-and-wave discharges; (h) photoparoxysmal response; (i) giant SEPs and hyperexcitability of the C-reflex; and (j) cortical EEG potential time-locked to the jerks. The original Japanese families linked to chromosome 8q23.3-q24 (Mikami et al., 1999). However, the European families with a similar phenotype did not link to the same locus (Labauge et al., 2002; van Rootselaar et al., 2002; Striano et al., 2004). Autosomal dominant cortical reflex myoclonus and epilepsy (ADCME) (Guerrini et al., 2001) has been described in patients with a homogeneous syndromic core including an association of nonprogressive cortical reflex myoclonus, cortical tremor, GTCs preceded in some patients by generalized myoclonic jerks, and generalized EEG abnormalities. Age at onset of cortical tremor and of GTCs overlapped in a given individual but varied between individuals, ranging from 12 to 50 years. This clinical picture shares some features with FAME; however all ADCME patients had in addition focal fronto-temporal EEG abnormalities and some also had focal seizures, of variable severity, starting at around the same age as the other manifestations. Linkage analysis identified a critical region in chromosome 2p11.1-q12.2 (Guerrini et al., 2001). Three Italian families with FAME exhibited a weak linkage to 2p11.1-q12.2,

suggesting a possible allelism with ADCME (De Falco et al., 2003; Striano et al., 2004).

EPILEPTIC SYNDROMES WITH SECONDARILY GENERALIZED EPILEPTIC MYOCLONUS

Severe myoclonic epilepsy in infancy (SMEI) or Dravet syndrome Dravet syndrome is observed in 6–7% of children with seizure onset in the first year of life (Dravet et al., 2002) and is characterized by multiple seizure types and an unfavorable prognostic outlook. Myoclonus, although present in most children, can be a transient phenomenon (Oguni et al., 2001; Dravet et al., 2002). Mutations or deletions/duplications of the SCN1A gene are observed in about 85% of cases (Marini et al., 2007, 2009). Onset of epilepsy occurs during the first year of life with prolonged generalized or unilateral, clonic seizures during fever, often evolving to status. They rapidly become associated with similar nonfebrile attacks. By the third to fourth year of life, resistant myoclonic, partial seizures, and atypical absences may appear. EEG, normal at the beginning, subsequently shows multifocal and generalized abnormalities. Early photosensitivity is seen in some children. Neurological development appears delayed from the second year of life onwards. Two main types of myoclonus have been described. Almost all children show arrhythmic, distal jerks, manifested as twitching of fingers, while some also have generalized jerks. Demonstrating a time-locked cortical potential for multifocal jerks may be difficult, even using jerk-locked averaging. Generalized jerks have an

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obvious EEG correlate, which appears to originate from spread of CM activity when small time differences are measured (Guerrini et al., 2005a). Lennox–Gastaut syndrome Lennox–Gastaut syndrome (LGS) has a prevalence of 2–3% in children with epilepsy and is often observed in the brain damaged (Arzimanoglou et al., 2009). Typical seizures start at 3–5 years of age as tonic, atonic, or atypical absences. Associated seizure types are myoclonic, generalized tonic–clonic, and, rarely, focal. Epilepsy is drug-resistant and episodes of status are frequent. Myoclonus is not a prominent feature of LGS (Gastaut, 1982), but some patients exhibit generalized myoclonic jerks that seem to be produced by a secondary generalization of focal CM (Bonanni et al., 2002). Minipolymyoclonus, a term used to describe distal, small focal jerks, frequently leading to individual tiny finger movements, is observed in some patients with LGS (Wilkins et al., 1985; Grosse et al., 2003) in which back-averaged EEG shows a bilateral frontal negative slow wave, with 20–500 ms latency. In other patients a sharper bilateral frontal negativity is demonstrable, leading the jerks by 40–70 ms (Wilkins et al., 1985). Minipolymyoclonus is strongly similar to cortical tremor (Grosse et al., 2003; Carr et al., 2007).

SUBCORTICAL^CORTICAL (THALAMOCORTICAL) MYOCLONUS: IDIOPATHIC (PRIMARY) GENERALIZED EPILEPTIC MYOCLONUS Generalized epileptic myoclonus is spontaneous, predominantly arrhythmic, and has an inconstant axial predominance. Patients may present with simple head nodding or raised shoulders, or may stagger or fall. The generalized jerks appear to originate from afferent volleys from subcortical structures that act synchronously on a hyperexcitable cortex (Gloor, 1979; Hallett, 1985). As a consequence, muscles from both sides are activated synchronously, as in reticular myoclonus, and muscles innervated by the cranial nerves are involved through a rostro-caudal pattern of activation, as in cortical myoclonus. The EEG correlate is a generalized spike-wave. The negative peak of the spike precedes the generalized jerks by 20–75 ms.

Idiopathic generalized epilepsies BENIGN MYOCLONIC EPILEPSY OF INFANCY Benign myoclonic epilepsy of infancy (BME), as originally described by Dravet et al. (1992), has been questioned as a definite syndrome. It affects 0.4% to 2% of all children with seizure onset by age 3 years (Dalla

Bernardina et al., 1983; Dravet et al., 1992; Guerrini et al., 1994). Age at onset ranges between 4 months and 5 years. Most children have normal development but some can exhibit mild cognitive impairment (Dravet, 1990; Dravet and Bureau, 2005). Seizures consist of generalized myoclonic jerks, which are brief, isolated, or repeated in small series. If the child is standing or sitting, the jerks often cause nodding with upward gaze deviation and eyelid myoclonus, accompanied by slight arm abduction or elbow bending. Staggering or falls may occur, especially within the second year of life, when walking is unstable. Jerks occur many times per day. A few patients may have generalized tonic–clonic seizures in adolescence (Dravet and Bureau, 2005). Treatment had been withdrawn in most patients aged more than 6 years at follow-up (Dravet, 1990). The term “benign” is questionable according to the most recent ILAE definitions in that outcome is often judged only in retrospect and children with the same clinical presentation at onset might have cognitive or behavioral sequelae (Engel, 2001; Guerrini and Aicardi, 2003). About 10% of children have photic-induced jerks (Dravet, 1990). Some have both spontaneous and reflex myoclonus triggered by tactile or sudden acoustic stimuli (Ricci et al., 1995). Neurophysiology of myoclonus reveals symmetrical, rostro-caudal muscle activation and a premyoclonus negative spike preceding jerks by 30 þ/ 2 msec (Guerrini et al., 2002a). Duration of the myoclonic jerk is roughly 100 ms.

JUVENILE MYOCLONIC EPILEPSY Juvenile myoclonic epilepsy (JME) has a prevalence of between 3.4 and 11.9% and represents the most common form of idiopathic generalized epilepsy (23.3%) (Thomas et al., 2000). The syndrome is genetically heterogeneous and in most cases is presumed to be polygenic. However, mutations of three different genes have been identified in rare families having dominant (CLCN2 and GABRA1) (Cossette et al., 2002; Haug et al., 2003; Annesi et al., 2007) or recessive (EFHC1) forms of the syndrome (Suzuki et al., 2004). Onset occurs at around age 14, with generalized myoclonus and generalized tonic–clonic seizures. Myoclonic jerks constitute the initial symptom in 54% of patients. They are characteristically concentrated in the minutes following awakening (Fig. 69.3), are bilateral, single or repetitive, arrhythmic, and more pronounced in the upper limbs. If intense, they may result in falls, but are too brief to be accompanied by loss of awareness. Facial or lingual and perioral jerks, usually isolated, may be precipitated by talking in some patients (Wolf and Mayer, 2000), a phenomenon analogous to the jerking observed in primary reading epilepsy. In 5% of patients, generalized jerks are also triggered by intermittent photic stimulation. Severe increase in

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L. Delt

R. Delt Fz-Cz 1 sec 100 mV

Fig. 69.3. A 20-year-old woman with juvenile myoclonic epilepsy. On the left: sleep EEG showing generalized polyspikeand-wave discharges. On the right: upon awakening, two generalized myoclonic jerks, accompanied by generalized polyspike-and-wave discharges, are recorded on eye closure.

frequency of jerks may herald episodes of myoclonic status epilepticus, which have become rarer (Thomas et al., 2000) with improved treatment. Drug withdrawal or inappropriate drug choice are among the main factors that may precipitate status (Thomas et al., 2000). Generalized tonic–clonic seizures are present in 84% of patients and represent the initial symptom in 35%. They are often preceded by a build up of generalized myoclonic jerks. In 27% of patients, absences are also present, occurring infrequently. Treatment with valproic acid in monotherapy or in association with clonazepam leads to total control of seizures in 80% of patients (Genton et al., 1994). Discontinuation of drug therapy is followed by a high rate of relapse (90%) (Genton et al., 1994). Neurophysiological analysis of myoclonus indicates that muscles from both sides are activated synchronously and those innervated by the cranial nerves are involved through a rostro-caudal pattern of activation. The EEG correlate is a generalized spike- or polyspike-wave at 3–5 Hz, in which the negative peak of the spike precedes the generalized jerk by 10–30 ms (Guerrini et al., 2002a). Duration of the EEG transient is
100 ms, and that of the myoclonic potential is less than 100 ms. A lateralized onset of the EEG transient has been suggested on the basis of an interside latency (9.5þ/1.7 ms) that was thought to be compatible with trans-callosal spread (Panzica et al., 2001). However, it remains to be explained why this supposed focal trigger constantly spreads to produce a generalized phenomenon, without any focal jerking, as usually seen, for example, in patients with PMEs who constantly exhibit both.

MYOCLONIC–ASTATIC EPILEPSY Myoclonic–astatic epilepsy (MAE) has its onset between 2 and 6 years of age. Seizure types include generalized myoclonus and atonic falls, atypical absences, generalized

clonic or tonic–clonic seizures, and episodes of status with erratic myoclonus and clouding of consciousness (Doose, 1992). Interictal EEG, often normal at onset, can become very disorganized (Guerrini and Aicardi, 2003). Outcome is unpredictable. Remission within a few months or years and normal cognitive skills are possible, even after a severe early course (Kaminska et al., 1999; Oguni et al., 2002). About 30% of children experience long-lasting intractability and cognitive impairment (Guerrini et al., 2005b). A handful of children with MAE have been shown to have inherited SCN1A and GABRG2 gene mutations from parents with generalized epilepsy with febrile seizures plus (Meisler et al., 2001). However, the genetics of MAE is complex. Myoclonus in MAE manifests as bilateral, synchronous whole body jerks, consistent with the hypothesis of a thalamo-cortical origin (Guerrini et al., 1998d). The jerks, lasting around 100 ms, are preceded by a negative EEG potential by around 30 ms (Bonanni et al., 2002). Myoclonic status has neurophysiological characters of erratic CM with multifocal jerking, increase in muscle tone, and clouding of consciousness. Nonconvulsive status may be precipitated by carbamazepine (Guerrini et al., 2002a). Treatment is primarily with valproate and ethosuximide, often in combination. Lamotrigine, topiramate, and benzodiazepines might be useful in some patients.

EPILEPTIC SYNDROMES WITH MYOCLONUS OF UNCLEAR NEUROPHYSIOLOGICAL CHARACTERIZATION Early myoclonic encephalopathy Early myoclonic encephalopathy is a rare syndrome. Its causes are multiple and include some inborn errors of metabolism such as methylmalonic acidemia and

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nonketotic hyperglycinemia. Onset is in the neonatal period or during the first month of life with severe myoclonus, followed by partial seizures and tonic spasms. Myoclonus has a multifocal distribution, leading to the definition of “erratic.” Neurological development is severely delayed, with hypotonia, impaired alertness, and, often, vegetative state (Aicardi, 1992). The EEG is characterized by suppression bursts. Erratic myoclonus generally does not have an EEG correlate (Aicardi, 1992).

Myoclonic status in fixed encephalopathies This condition is seen exclusively in severe encephalopathies with profound cognitive impairment and hypotonia, and is characterized by recurrent, prolonged, and drug-resistant episodes of myoclonic status (Dalla Bernardina et al., 2005). Partial motor seizures, myoclonic absences, generalized myoclonus, and, rarely, unilateral or generalized clonic seizures can be associated. Myoclonic status is characterized by almost continuous absences accompanied by erratic, distal, multifocal, frequent myoclonic jerks, at times more rhythmic and diffuse. It is extremely important to recognize this condition and to differentiate it from a progressive encephalopathy.

Epilepsy with myoclonic absences Myoclonic absences as a seizure have been reported in different clinical contexts. However, there appears to be a relatively homogeneous group of children in which a syndrome core can be delineated with onset at 7 years of age, absences recurring many times a day, accompanied by bilateral rhythmic jerks, involving the shoulders, arms or legs and, eventually, by a mild axial tonic contraction. Consciousness is cloudy but not completely interrupted (Tassinari et al., 1992). Ictal EEG shows bilateral, synchronous, and symmetrical spike-wave discharges at 3 Hz and myoclonic jerks at the same frequency. Absences are often resistant to treatment. Evolution is variable featuring cognitive impairment in some patients, transition to a different type of epilepsy, or at times full recovery without sequelae. The physiology of myoclonus in myoclonic absences is difficult to study as jerks appear against a background of increased muscle tone (Guerrini et al., 2002a). Tassinari and coworkers (Tassinari et al., 1995a) found a constant relationship between the spike-and-wave complex and the jerk, with the positive spike of the spike-and-wave complex being followed by a myoclonic jerk with a latency of 15–40 ms (proximal muscles).

Eyelid myoclonia with and without absences Eyelid myoclonia with absences are characterized by prominent jerking of the eyelids with upward deviation of the eyes. Some authors (Jeavons, 1982) emphasized the severity of eyelid jerking in these patients as compared with the slight flicker of the eyelids seen in typical absences. The phenomenon may be so short (1–2 seconds) that it may be impossible to find out whether there is concomitant lapse of consciousness. The intensity of the jerking justifies the inclusion of this condition within the group of myoclonic epilepsies, the more so as the myoclonic phenomena are difficult to control and persist into adulthood, whereas the absences are relatively easily controlled. A marked photosensitivity and selfstimulation are features that eyelid myoclonia, with and without absences, share with other myoclonic epilepsies of infancy and childhood.

Myoclonic seizures induced by photic stimuli Myoclonic attacks can be induced by photic stimuli. Jeavons and Harding (Jeavons and Harding, 1975) found that only 1.5% of pure photosensitive epilepsies (i.e., epilepsies induced exclusively by exposure to visual stimuli without any spontaneous attacks) were myoclonic. Visually induced generalized myoclonic jerks are usually symmetrical and predominate in the upper limbs. In most cases they are mild, only producing head nodding and slight arm abduction. More generalized jerks, involving the face, trunk, and legs may occasionally cause the patient to fall. The relationship of myoclonic jerks to the stimulus is complex. Sometimes there is no definite time relationship. On other occasions, the jerks may be repeated rhythmically with the same frequency as the stimulus or at one of its subharmonics (Kasteleijn-Nolst Trenite et al., 2001). The jerks are associated on the EEG recording with the photoparoxysmal response, consisting of a bilateral polyspike or polyspike-and-wave discharge (Gastaut and Broughton, 1972; KasteleijnNolst Trenite et al., 2001). Spontaneous seizures are said to occur mainly, but not exclusively, when the polyspike-wave discharge persists after discontinuation of the stimulation (“prolonged photoconvulsive response”) (Reilly and Peters, 1973). Myoclonic attacks can be provoked by television watching, especially when the patients are close to the screen and while playing video-games. Some patients induce the myoclonic attacks by waving a hand between their eyes and a source of light, flickering their eyelids in front of a light source or staring at patterned surfaces, or by similar maneuvers (Jeavons and Harding, 1975; Binnie et al., 1980; Tassinari et al., 1990). There is no clearcut nosological distinction between eyelid myoclonia and photic-induced myoclonus.

MYOCLONUS AND EPILEPSY

RETICULAR REFLEX MYOCLONUS Reticular myoclonus presents most of the clinical and neurophysiological characteristics of epileptic myoclonus although it lacks a time-locked EEG correlate (Hallett, 1985). Clinically, myoclonic jerks are generalized, mostly involving proximal and flexor muscles, spontaneous, or induced by somatosensory, auditory and visual stimuli, or by movement (Hallett et al., 1977; Hallett, 1985). Reticular myoclonus seems to originate from the brainstem reticular formation, as involvement of trapezius and sternocleidomastoid muscles (innervated by XIth cranial nerve) precedes that of orbicularis oris and masseter (innervated by VIIth and Vth cranial nerves) (Hallett et al., 1977). EEG discharges have a wide distribution and greater amplitude at the vertex and can follow the onset of the jerks, suggesting that they are projected and not directly responsible for the myoclonic jerks (Hallett, 1985). SEPs have normal amplitude. In reflex reticular myoclonus both slow and fast conducting pathways have been observed (Rothwell et al., 1986). Reticular myoclonus has been described in postanoxic encephalopathy, and can appear alongside cortical myoclonus in some patients (Hallett et al., 1979; Brown et al., 1991b). In patients with progressive myoclonus epilepsy a form of focal subcortical reflex myoclonus has been described, whose latencies might be consistent with origin in the reticular formation (Cantello et al., 1997). Neurophysiological study of reticular reflex myoclonus is, however, difficult, especially because of the coexistence of cortical myoclonus in most patients. As a consequence its neurophysiological correlates and relationships with epilepsy are poorly understood. Electrophysiological recordings in urea-induced myoclonus in the rat, which is considered to be a model of reticular reflex myoclonus, have demonstrated neuronal activity resembling paroxysmal depolarization shift in the nucleus reticularis gigantocellularis (Zuckermann and Glaser, 1972).

ANTIEPILEPTIC DRUG-INDUCED MYOCLONUS Antiepileptic drugs can aggravate or induce myoclonus or myoclonic seizures, either because of paradoxical reaction or inappropriate choice. Carbamazepine and vigabatrin have been reported to worsen or precipitate myoclonic seizures (Talwar et al., 1994; Viani et al., 1995). De novo appearance of myoclonic jerks was described in children or young adults with cryptogenic or symptomatic partial epilepsy treated with add-on vigabatrin (Lortie et al., 1993; Marciani et al., 1995). Carbamazepine should be avoided in MAE, because it can trigger episodes of myoclonic status (Guerrini et al., 2002a).

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Adolescents with juvenile absence epilepsy may experience myoclonic status if treated with carbamazepine when their absence seizures are misdiagnosed as complex partial seizures (Marini et al., 2005). Exacerbation of epileptic negative myoclonus has been reported in children with benign rolandic epilepsy after carbamazepine treatment (Guerrini et al., 1998c; Parmeggiani et al., 2004). Lamotrigine may be useful in some children with myoclonic-astatic epilepsy (Dulac and Kaminska, 1997), but has been reported to worsen Dravet syndrome (Guerrini et al., 1998c) and, occasionally, to precipitate seizure aggravation and de novo myoclonic status epilepticus if administered at high doses in other conditions (Briassoulis et al., 1998; Guerrini et al., 1999; Biraben et al., 2000; Janszky et al., 2000; Carrazzana and Wheeler, 2001). Lamotrigine has also been reported to aggravate seizures in patients with JME (Biraben et al., 2000). In Angelman syndrome worsening of myoclonic and absence seizures may be produced by carbamazepine, oxcarbazepine (Laan et al., 1997; Minassian et al., 1998; Vendrame et al., 2007), phenytoin (Minassian et al., 1998), or vigabatrin (Kuenzle et al., 1998).

CONCLUSION Epileptic myoclonus can be defined as an elementary electroclinical manifestation of epilepsy involving descending neurons, whose spatial (spread) or temporal (self-sustained repetition) amplification can trigger overt epileptic activity (Guerrini et al., 2002a) and can be classified as cortical (positive and negative), secondarily generalized, thalamo-cortical, and reticular (Guerrini et al., 2005a). Cortical epileptic myoclonus represents a fragment of partial or symptomatic generalized epilepsy; thalamo-cortical epileptic myoclonus is a fragment of idiopathic generalized epilepsy (Hallett, 1985). Reflex reticular myoclonus represents the clinical counterpart of fragments of hypersynchronous epileptic activity of neurons in the brainstem reticular formation. Epileptic myoclonus, in the setting of an epilepsy syndrome, can be only one component of a seizure (i.e., myoclonic build up in the clonic–tonic–clonic seizures of juvenile myoclonic epilepsy), the only seizure manifestations (myoclonic seizures of benign myoclonic epilepsy), one of the multiple seizure types (myoclonic– astatic seizures in childhood epileptic encephalopathies), or a more stable condition that is manifested in a nonparoxysmal fashion and mimicks a movement disorder (i.e., the continuous jerking of cortical tremor or of epilepsia partialis continua or the movement activated jerks of progressive myoclonus epilepsy that can translate into a myoclonic cascade and a full blown generalized tonic–clonic seizure). This complex correlation is

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