Progressive Myoclonus Epilepsies (PMEs)

Progressive myoclonus epilepsies represent a clinically and etiologically heterogeneous group of diseases with a progressive course, characterized by myoclonus, generalized, tonic-clonic seizures, and neurological deterioration.⁴⁸ Onset is most frequently in late childhood or adolescence.⁴⁹ Different forms are known, including Unverricht-Lundborg disease, Lafora disease, neuronal ceroid-lipofuscinosis, type III Gaucher disease, infantile and juvenile GM2-gangliosidosis, some mitochondrial encephalopathies, sialidosis, dentatorubropallidoluysian atrophy, and action myoclonus-renal failure (AMRF).^49,50 Causative genes have been identified for most PMEs.^51,52 Onset features comprise myoclonus and rare generalized tonic-clonic seizures, as in idiopathic myoclonic epilepsies.^53,54 The tonic-clonic seizures can occur without any warning or after a long buildup of myoclonic jerks. The EEG shows generalized polyspike and spike-and-wave discharges, frequently precipitated by photic stimulation. Background EEG activity becomes progressively slower.⁵³ Cortical reflex myoclonus is common to all PME syndromes, in which it is manifested with the classic combination of action myoclonus (Figure 8-1), spontaneous jerks, giant SEPs, C-reflex at rest, and the premyoclonus spike. According to Cantello et al.,⁵⁵ 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.

Figure 8–1 Twenty-seven-year-old woman with sialidosis (cherry red spot myoclonus) and movement-activated seizures. When the patient raises her right arm to seize an object, there is a typical “cascade” of myoclonic potentials that is initially arrhythmic and involves all sampled muscles on the right (right deltoid, wrist extensors, and flexors), then become more rhythmic and spread to the contralateral muscles. This pattern of spread of myoclonic activity is typical of action myoclonus.

Rett Syndrome

Rett syndrome is an X-linked dominant disorder, with an estimated prevalence of 1 in 10,000 to 15,000 females, making it one of the most common causes of severe mental retardation in females. Mutations in the exons 1 to 4 of the methyl CpG binding protein 2 gene (MECP2)⁵⁶ have been identified in roughly 75 to 80% of girls with classical Rett syndrome;⁵⁷ in MECP2-negative patients additional screening using (multiplex ligation probe amplification) MLPA enables detection of large deletions in nearly half of the remaining patients with the syndrome.⁵⁸ The clinical phenotype 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 ± 5 msec) latency has been described in affected girls.⁵⁹ Myoclonus is multifocal and arrhythmic, and major myoclonic seizures are not seen in these patients. A positive potential, localized on the contralateral centroparietal area, precedes myoclonus with a latency of 34 ± 7 msec 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 = 11 msec), delay in corticocortical transmission to the precentral neurons subserving movement of the stimulated body segment (latency increase P30 – C reflex; mean = 32 msec), and rapid descending volley to the spinal motoneurons. Intracortical conduction time could be particularly prolonged because of the synaptic abnormalities that have been observed.⁶⁰

Huntington’s Disease

In Huntington’s disease, action myoclonus is a rare manifestation, but a few patients have been described in whom CRM was the presenting symptom.^33,61 Seizures are an infrequent complication and are mainly seen with juvenile onset, rarely presenting with a typical PME syndrome.⁶²

Postanoxic Encephalopathy

Postanoxic encephalopathy is characterized by dysarthria, ataxia, pyramidal signs, rigidity, epilepsy, and myoclonus, which is usually spontaneous and action-induced, multifocal and generalized, and extremely disabling. Electromyographic silent periods following the jerks contribute to producing postural lapses.⁶³ Postanoxic myoclonus may be cortical in origin, involving the sensorimotor cortex and rapidly conducting pyramidal pathways.^14,28 More rarely it may have brainstem origin, either as an exaggerated startle reflex or as reticular reflex myoclonus.^64,65 Forty percent of patients with postanoxic myoclonus suffer from generalized epileptic seizures.

Epilepsia Partialis Continua

Epilepsia partialis continua, or Kojewnikow’s syndrome,⁶⁶ is characterized by almost continuous, focal, rhythmic (around 1 to 2 Hz) muscle jerks, which are observed both while awake and asleep, for periods ranging from hours to days, or rarely years.⁴⁸ Unilateral somatomotor seizures are constantly associated. Two types of epilepsia partialis continua have been identified.⁶⁷ 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.^67–70 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. Magnetic resonance imaging (MRI) shows progressive atrophy of the affected hemisphere. Pathological studies reveal inflammation with perivascular infiltrates and microglia nodules.⁷¹ A viral etiology was originally hypothesized. More recently, the role of antibody-mediated mechanisms and more recently cell-mediated immunity have been hypothesized^72,73,74 with inconclusive results. An analogous form of progressive epilepsia partialis continua has been observed in some children with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS).⁷⁵

Angelman Syndrome

Angelman syndrome is a neurogenetic disorder deriving from a defect in maternal chromosome 15q11 to q13. Seventy percent of patients present a cytogenetic or molecular deletion encompassing three subunits of receptor α for gamma-aminobutyric 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 microbrachycephaly, severe to moderate mental retardation, absence of speech, inappropriate paroxysmal laughter, epilepsy, ataxic gait, tremor, and jerky movements. Neurophysiologic investigations reveal a spectrum of manifestations of myoclonus.⁸⁴ All patients present with rapid distal jerking of fluctuating amplitude, which causes a sort of coarse distal tremor combined with dystonic limb posturing. Jerks occur at rest in prolonged runs. In addition, the majority of patients have 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 corticospinal 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 myoclonus manifested as cortical tremor has been described in several families, mostly of Japanese origin,^79,85 and given the acronym BFAME (benign familial adult myoclonic epilepsy) or FAME (familial adult myoclonic epilepsy). Affected patients present homogeneous characteristics, including (a) autosomal dominant inheritance; (b) adult onset (mean age 38 years, range: 19 to 73); (c) nonprogressive course; (d) distal, rhythmic myoclonus enhanced during posture maintenance (cortical tremor); (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 (Figure 8-2); and (j) cortical EEG potential time locked to the jerks. The original Japanese families linked to chromosome 8q23.3-q24.⁸⁶ However, European families with a similar phenotype did not link to the same locus.^85,87,88

Figure 8–2 Young adult lady with autosomal dominant cortical myoclonus and epilepsy. Cortical SEP to electrical stimulation of the left median nerve at the wrist. An enlarged N20-P30-N35 complex is followed by C-reflex in the left deltoid, wrist extensors, and abductor pollicis brevis. The ipsilateral muscular response precedes a contralateral response by ∼ 8 ms. This delay is consistent with inter-hemispheric transcallosal spread. L = left; O. Oris = orbicularis oris; Delt = deltoid; W. Ext = wrist extensors; APB = abductor pollicis brevis; C = cortical reflex; TA = tibialis anterior; R = right; ClC = contralateral cortical reflex.

Autosomal dominant cortical reflex myoclonus and epilepsy (ADCME)⁸¹ has been described in patients with a homogeneous syndromic core, including an association of nonprogressive cortical reflex myoclonus, manifested as semicontinuous rhythmic distal jerking (cortical tremor), generalized tonic-clonic convulsions (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 FAME⁸⁶; however, all ADCME patients had in addition focal frontotemporal EEG abnormalities, and some individuals also had focal seizures, of variable severity, starting around the same age as the other manifestations. The pattern of inheritance is autosomal dominant with high penetrance. Linkage analysis identified a critical region in chromosome 2p11.1-q12.2.⁸¹ Three Italian families with familial adult myoclonic epilepsy have been described, possibly linked to 2p11.1-q12.2, suggesting a possible allelism with ADCME.^88,89

Recently two novel families with adult myoclonic epilepsy have been reported,^82,83 neither linking to known loci. In the first report, clinical photosensitivity was a prominent feature; in the second report photosensitivity was not a prominent feature, but cerebellar ataxia, dementia, and progression of symptoms were observed, raising doubts about the nosology of this disorder.

Severe Myoclonic Epilepsy in Infancy (SMEI), or Dravet Syndrome

SMEI, or Dravet syndrome, is observed in 6 to 7% of children with seizure onset in the first year of life⁹⁰ and is a severe form of epilepsy, characterized by multiple seizure types and unfavorable prognostic outlook. Its classification as a form of myoclonic epilepsy is controversial because myoclonus, although present in most children, can be a transient phenomenon and often does not represent a hallmark of the syndrome. A subgroup of children does not exhibit myoclonic seizures at all.^90,91 SMEI represents the prototype of an epileptic encephalopathy in which onset of severe, prolonged seizures precedes deterioration of cerebral functions.⁹² Mutations of the SCN1A gene are observed in about 80% of cases.⁹³ Onset of epilepsy occurs during the first year of life with prolonged generalized or unilateral, clonic or tonic-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 also 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 onward. Two main types of myoclonus have been described. Almost all children show arrhythmic, distal jerks, manifested as twitching of fingers, whereas some also have generalized jerks. Demonstrating a premyoclonic potential for multifocal jerks may be difficult, even using jerk-locked averaging. Generalized jerks have an obvious EEG correlate, which appear to originate from spread of CM activity, when small time differences are measured (Figure 8-3).^10,54

Figure 8–3 Fourteen-year-old boy with severe myoclonic epilepsy. Polygraphic recording. A discharge of bilateral and synchronous quasi-rhythmic multiple spike and waves and spike-and-wave complexes is accompanied by a series of myoclonic potentials, most of which are only visible on the left masseter. Muscle jerks are time locked with the spikes; one jerk is generalized. Such focal jerks, which were not reported by the patient, would have gone unrecognized should multiple muscles not have been sampled.