chapter 240 epilepsy with myoclonic absences

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CHAPTER 240 ■ EPILEPSY WITH MYOCLONIC ABSENCES CARLO ALBERTO TASSINARI, ROBERTO MICHELUCCI, ELENA GARDELLA, AND GUIDO RUBBOLI

INTRODUCTION Epilepsy with myoclonic absences (MAs) is an epileptic syndrome clinically characterized by absence seizures associated with rhythmic, bilateral myoclonic jerks of severe intensity. The diagnosis is based on clinical observation and ictal video-polygraphic recordings. Indeed, in video-polygraphic investigations (collecting an electroencephalogram [EEG] and electromyogram [EMG] from upper limb muscles, such as deltoids), MAs are characterized by rhythmic, bilateral, synchronous, symmetric 3-Hz spike-wave (SW) discharge, as in typical absences, associated with EMG myoclonic bursts at 3 Hz, superimposed to a progressively increasing tonic contraction. Demonstration of MA seizures is essential for the diagnosis; thus, epilepsy with MAs belongs to the group of epilepsy syndromes that is defined by a specific seizure type (as, for example, juvenile myoclonic epilepsy or myoclonic astatic epilepsy [Doose syndrome]). Indeed, since the early description of MAs,13,15,16 it has been believed that this seizure type could characterize a distinct epileptic condition that could be identified and separated from other forms of generalized epilepsy, such as childhood absence epilepsy. The Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) accepted this view, recognizing epilepsy with MAs as an autonomous syndromic entity that was included, in the 1989 ILAE Proposal for Revised Classification of Epilepsies and Epileptic Syndromes,6 in the group of cryptogenic or symptomatic generalized epilepsies, due to an overall dismal and heterogeneous prognosis. On the other hand, in the more recent Proposed Diagnostic Scheme for People with Epileptic Seizures and with Epilepsy produced by the ILAE Task Force on Classification and Terminology,9 it has been tentatively placed among idiopathic generalized epilepsies. Recent reviews on this epileptic condition by Bureau and Tassinari2,3 and Tassinari et al.21 acknowledged the existence of at least two forms of epilepsy with MAs: One with a more benign course, and eventually disappearance of seizures, in which MAs are the sole, or predominant, seizure type; and the other with MAs associated with other seizure types (particularly, frequent generalized tonic–clonic seizures) that bears a more severe prognosis, as compared to other idiopathic generalized epilepsies. Furthermore, cases with “atypical” features in which MAs were part of a clinical picture characterized by some degree of mental retardation, neurologic deficits (e. g., congenital hemiparesis), and chromosomopathy7,8,11 have been reported.

CLINICAL DATA General Remarks Epilepsy with MAs is a rare condition; in a selected population of epileptic patients attending the Centre St. Paul in Marseilles, it accounts for 0.5% to 1% of all epilepsies. There is a male preponderance (69%), at variance with childhood absence epilepsy in which females are more frequently affected. Etiologic factors reported in about 35% of cases are prematurity, perinatal damage, consanguinity, congenital hemiparesis, and chromosomopathy.2,3 The evidence in some cases of associated chromosomal dysfunction has led to the hypothesis that abnormal expression of genes located in the affected chromosome segments may play a role in the pathogenesis of myoclonic absence epilepsy.7,8 A genetic susceptibility, as demonstrated by a positive family history of epilepsies, has been observed in about 20% of cases. The mean age of onset of MAs is 7 years, with a range between 11 months and 12.2 years. Reports describing cases with onset of MAs in the first year of life have been published in the last years.1,14,19,22

Myoclonic Absences MAs are characterized by the following: Impairment of consciousness, which can vary in intensity, ranging from a mild disruption of contact to a complete loss of consciousness. Sometimes the patients are aware of the jerks and may recall the words pronounced by the examiner during the seizures. Motor manifestations, which consist of bilateral myoclonic jerks, often associated with a discrete tonic contraction that has been clearly documented in proximal upper limb muscles. The myoclonias mainly involve the muscles of the shoulders, arms, and legs; facial myoclonias, when present, are more evident around the chin and the mouth, whereas eyelid twitching is typically absent or rare. Due to concomitant tonic contraction, the jerking of the arms is accompanied by a progressive elevation of the upper extremities, giving rise to a quite constant and recognizable pattern. When the patient is standing, falling is uncommon. In some patients, asymmetric features, such as head and trunk deviation, may occur.

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Autonomic manifestations, which consist of an arrest of respiration and inconstant loss of urine. MAs last for 10 to 60 seconds, and recur at a high frequency (many seizures per day), being often precipitated by hyperventilation or awakening. MAs may also be observed during the early stages of sleep. Episodes of MA status are distinctly rare.

Seizures Other Than Myoclonic Absences MAs represent the only seizure type in about one third of patients. The remaining cases can suffer from other seizure types, which can appear before the onset MAs or occur in association with MAs. They consist of generalized tonic–clonic seizures, absences, or epileptic falls.

Neurologic and Neuropsychologic Examination Neurologic examination is normal, except in those cases with congenital hemiparesis. Mental retardation is present in about 45% of cases before the onset of MAs. During the course of MAs, mental retardation may worsen, or even appear, in patients previously normal, particularly in those patients with frequent tonic–clonic seizures associated with MAs. These data constitute a very significant difference for this subgroup of patients when compared with the cognitive status observed in childhood absence epilepsy.

NEUROPHYSIOLOGIC DATA Interictal EEG The interictal EEG shows a normal background activity in all cases. In one third of cases, bursts of generalized SWs or, more rarely, focal or multifocal SWs are present. It is noteworthy to point out that the sinusoidal posterior slow rhythm has never been observed, as reported in childhood absence epilepsy.

Ictal EEG The ictal EEG consists of rhythmic SW discharges at 3 Hz, which are bilateral, synchronous, and symmetric, as observed in typical absences. The onset and the end of SWs are abrupt. Polygraphic (EEG-EMG) recording discloses the appearance of bilateral myoclonias, at the same frequency as the SW, which begin around 1 second after the onset of EEG paroxysmal discharges and are followed by a tonic contraction, maximal

FIGURE 1. Spontaneous myoclonic absence. Electroencephalogram (EEG): Rhythmic spike-wave (SW) discharge at 3 Hz, bilateral, synchronous, and symmetric, as observed in typical absences. Electromyogram (EMG): Rhythmic myoclonia, at the same frequency of the SW, involving the upper extremities, and starting about 1.5 seconds after the onset of the EEG paroxysmal discharge, associated with a tonic contraction with progressively increasing intensity. Delt., deltoid; W.Flex., wrist flexor; W.Ext., wrist extensor; R., right; L., left.

in the shoulder and deltoid muscles (Fig. 1). Original investigations by Tassinari et al.16,17 by means of high-speed oscilloscopic analysis provided a detailed description of the relationships between the EEG SW and motor events, showing a strict and constant relation between the spike of the SW discharge and the myoclonia (Fig. 2). These studies emphasized the relationships between the positive transient encompassed in the SW complex,24 which in MAs is of high amplitude and is followed on the EMG by a myoclonia with a latency of 15 to 40 msec for the more proximal muscles and of 50 to 70 msec for the more distal muscles. This myoclonia is itself followed by a brief silent period (60 to 120 msec), which breaks the tonic contraction. Recently, Gardella et al.10 demonstrated that the first myoclonic jerks were restricted to the facial musculature, then spreading to the neck and upper limbs muscles. Back-average of the EEG activity triggered from the onset of the first myoclonia confirmed the correlation of the

FIGURE 2. High-speed polygraphic recording of a myoclonic absence (MA) seizure, showing the relationship between the spike of the spikewave (SW) complex and the myoclonic potential. The first three SW complexes are not associated with any evident myoclonic activity. Delt., deltoid; W.Flex., wrist flexor; W.Ext., wrist extensor; L., left

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EVOLUTION Classical data on the evolution of MAs indicate that these are still present in about two thirds of the cases followed up for a mean period of 10 years, whereas they disappear in the remaining patients after a mean period of 5.5 years from the onset.2,3,21 The two groups of patients differ in the frequency and type of associated seizures: In fact, patients with “refractory” MAs have a high incidence (80%) of associated seizures, mainly of generalized tonic–clonic and atonic types. On the contrary, patients with remitting MAs have a lower incidence (40%) of associated seizures, mainly of the absence type. The long duration of MAs is likely to be an important factor for the appearance of mental retardation, since intellectual functions are always preserved in children with rapid remission of MAs. In rare cases, the disappearance of MAs has been followed by the onset of other seizure types, namely absences with atypical SW charges and clinical and subclinical tonic seizures, giving rise to a clinical picture similar to the Lennox-Gastaut syndrome.19,20

DIAGNOSIS

FIGURE 3. Tonic seizure during light sleep in a 45-year-old patient who started to suffer from myoclonic absences when she was 11 years old. Tonic muscular activity appears about 1 second after the onset of a rhythmic polyspike discharge. Delt., deltoid; R., right; L., left

Fig. 3

myoclonic phenomenon with the positive transient of the SW complex. Physiopathogenetic hypotheses on the peculiar muscular pattern that characterizes MA seizures admit that the tonic muscular contraction component that is superimposed on the myoclonic activity might be related to the involvement of secondary motor areas,3 possibly in the frontomesial cortex.12 Indeed, tonic contractions occur always in MAs, but after the appearance of few SW complexes, possibly suggesting a spread of paroxysmal activity to frontomesial areas. During the evolution, some cases may evolve to a “Lennox-Gastaut–like syndrome” with tonic seizures, particularly during wakefulness or light sleep, associated in the EEG with rhythmic polyspike waves (Fig. 3). In these patients, the disappearance of SW complexes might be observed, replaced by focal frontal spikes; although infrequently, a frontal partial status may occur that can be controlled by phenytoin administration.

Sleep EEG Sleep organization is constantly normal and physiologic patterns are symmetrically present. During sleep the evolution of the SW discharges is similar, on the whole, to that observed in childhood absence epilepsy.18 MAs may occur during stage I of sleep, awakening the subject. During stage II, SW discharges, of brief or long duration, are also observed, sometimes associated with bursts of myoclonias.

The diagnosis of MAs mainly rests on the polygraphic demonstration of SW discharges at 3 Hz (as in typical absences) accompanied by rhythmic myoclonias. Therefore, polygraphic recording is mandatory when the clinical suspicion of MAs is raised. Since the anamnestic data may sometimes be misleading (asymmetric MAs may be misdiagnosed as partial motor seizures, MAs with mild myoclonias may be misdiagnosed as typical petit mal absences, etc.), we suggest that polygraphic recording should be performed also in patients with “drugresistant” absence seizures and in cases with refractory “myoclonic” or “partial motor seizures.” Capovilla et al.4 reported a group of patients with childhood absence epilepsy exhibiting absence seizures associated with mild myoclonic jerks, involving mainly the facial and neck muscles (eyebrows, nostrils, perioral region, chin, sternocleidomastoideus). Indeed, the electroclinical characteristics (particularly, benign course with excellent response to treatment, and possible drug withdrawal in the evolution, and mild myoclonia without a background of tonic contraction) differentiate this clinical picture from epilepsy with MAs. Moreover, myoclonic phenomena have also been described in children with early-onset typical absences (before age 2 to 3 years).5 Finally, MAs must be differentiated from absence seizures with more or less rhythmic myoclonias associated with 2.5Hz irregular SWs observed in nonspecific diffuse epileptic encephalopathies.20

TREATMENT Data on outcome suggest that the correct medical therapy for MAs consists of the associated use of valproic acid and ethosuximide at high doses, with serum plasma levels ranging from 80 to 130 μg/mL and 70 to 110 μg/mL, respectively. Recent studies found lamotrigine, particularly in combination with valproate, or in one case ethosuximide, to be useful when other measures had failed.14,23 In individual cases, good seizure control was achieved by using a combination of phenobarbitone, valproic acid, and benzodiazepines. It must be pointed out that since epilepsy with MAs is a relatively rare condition, no comparative or controlled clinical trials have ever been performed; therefore, the only available data are of retrospective nature. In particular, the efficacy of more recent antiepileptic drugs that are currently used in the treatment of

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refractory absences or in myoclonic epilepsies, such as levetiracetam, topiramate, and zonisamide, has not been adequately investigated in epilepsy with MAs. Finally, it should be mentioned that drugs such as carbamazepine or phenytoin (and possibly vigabatrin, gabapentin, tiagabine, and oxcarbazepine) might theoretically worsen MAs; however, as above mentioned, in patients who present with partial status, phenytoin may be useful to stop seizure activity.

5. 6. 7. 8.

SUMMARY AND CONCLUSIONS The syndrome of epilepsy with MAs is a distinct form of childhood epilepsy characterized by a peculiar seizure type that identifies this epileptic condition. Recognition of MAs relies on direct clinical observation and polygraphic recording; in particular, the EEG-EMG ictal pattern bears specific features that allow differential diagnosis with other generalized seizure types. It can be stated that the demonstration of MAs is sufficient for the diagnosis. Regarding the natural history and prognosis of epilepsy with MAs, two forms may be identified: A form in which MAs are the sole or predominant seizure type and a form in which MAs are associated with other seizure types and particularly with numerous generalized tonic–clonic seizures; this latter form bears a poor prognosis in terms of seizure control and neuropsychological deterioration.

ACKNOWLEDGMENTS We thank Prof. G. Avanzini and Prof. S. Franceschetti from the Neurological Institute, “C. Besta,” in Milan for providing the case illustrated in Figure 1, and Mrs. C. Giardini for her help in the preparation of the manuscript.

9. 10. 11. 12. 13.

14. 15. 16. 17. 18.

19.

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