Epilepsy with myoclonic–astatic seizures (EMAS) is a recently identified type of idiopathic, potentially severe epilepsy. It is characterized by a combination of seizures, including drop attacks, and psychomotor deterioration beginning in early childhood. These features are similar to those of Lennox-Gastaut syndrome, and the syndrome’s nosologic limits, particularly with regard to the Lennox-Gastaut syndrome, are still not clearly determined. A “myoclonic variant of Lennox-Gastaut syndrome” has even been reported that most likely corresponds to one subtype of EMAS. Epilepsy with myoclonic–astatic seizures was identified on the basis of two distinct approaches by two different schools of epileptology: German researchers in Kiel identified genetic predisposition as an etiologic factor in severe pediatric epilepsy at the same time that researchers in Marseille were developing the concept of epilepsy syndromes.⁵ A clear definition therefore needs to be established distinguishing EMAS from both the Lennox-Gastaut syndrome and other kinds of myoclonic epilepsy occurring in childhood.⁸

In this chapter, we describe the development of EMAS as a syndrome, delineate it nosologically, describe the specific pattern of cognitive and motor dysfunction, define the therapeutic strategy, and describe the present pathophysiologic hypo- theses.

To understand the apparent contradictions that have paved the way for the identification of EMAS, one has to consider two major schools of epileptology following parallel pathways. The German school—Janz and Christian for adults⁹ and Doose and coworkers for children—was making considerable effort to clarify the genetic basis of epilepsy.⁷ Careful neurophysiologic analysis played a major role, particularly for children. Doose established a correlations between several electroencephalographic (EEG) patterns and familial antecedents of epilepsy, namely theta rhythms, generalized spike waves, spontaneous or triggered by hyperventilation, and photosensitivity (for a review, see Doose⁶). This allowed him to identify epilepsy conditions affecting early childhood that were thought to be due to genetic predisposition with polygenic inheritance. He called this group, in which myoclonic seizures causing drop attacks were a predominating feature, “centrencephalic myoclonic–astatic petit mal.”⁷ The main practical interest in the recognition of this group was to show that children with severe epilepsy involving the whole brain and producing drop attacks and cognitive deterioration did not all have Lennox-Gastaut syndrome, and thus some kind of brain lesion, but they could have genetically inherited epilepsy in an undamaged brain.

Patients within “centrencephalic myoclonic–astatic petit mal (CMAPM)” exhibited a range of different types of seizures: tonic–clonic, myoclonic, myoclonic–astatic, tonic, absence, and various types of epilepsy status, mainly myoclonic and absence. However, within this group, Doose distinguished various patterns correlated with different courses⁵:

Therefore, although CMAPM features myoclonic seizures and generalized spike-waves, which are assumed to express genetic predisposition, it is completely heterogeneous in terms of clinical presentation, EEG characteristics, and outcome. It is thus not a syndrome, but an etiologic concept of difficult-to-treat generalized epilepsies resulting from genetic predisposi-tion.

In the meantime, the Marseille school developed the concept of epilepsy syndromes following the observation that patients with epilepsy have a variable course ranging from full recovery to pharmacoresistance with major impact on cognitive and motor functions, and that this variability is not related solely to age of onset, seizure type, interictal EEG, or etiology. Indeed, etiology is identified in only one fourth of patients, and the variability also affects both patients without identifiable etiology and those with a given etiology. The type of seizure is not linked to etiology or the course because a given seizure type may occur in epilepsies with the most benign as well as those with the most severe outcome. Children with epilepsy usually exhibit several types of epileptic seizures, and therefore it is not possible to distinguish the various types of epilepsy according to seizure types only. In addition, the neurologic condition prior to onset of seizures, the age of onset, and the interictal clinical and EEG phenomena also vary greatly. However, there are groups of patients that have similar age of onset, seizure types, interictal EEG pattern, and course. These characteristics form the basics of epilepsy syndromes. This concept appeared soon after the clinical introduction of EEG. It became possible to distinguish between two major EEG patterns of generalized spike waves, respectively “petit mal” and “petit mal variant” patterns, which were correlated with different seizure types and distinct courses. In addition, the “hypsarrhythmic” EEG
pattern was linked to infantile spasms. This approach to the separation of various epilepsy patterns with distinct courses was then systematized in Marseille. In Lennox-Gastaut syndrome, drop attacks result from tonic seizures or atypical absences, whereas myoclonic seizures are rare. Therefore, it differs from conditions that include mainly myoclonic seizures. When myoclonic epilepsy has begun in infancy without any identifiable cause, two groups with respectively severe (Dravet syndrome) and benign courses could be distinguished. In the last decade of the twentieth century, it became clear that these two conditions were included in Doose’s “centrencephalic myoclonic–astatic petit mal.”

In addition, in some patients, “centrencephalic myoclonic–astatic petit mal” starts later in life, after the age of 2 years, in which severe myoclonic seizures cause the patient to fall, as in Lennox-Gastaut syndrome. Indeed, that can be difficult to distinguish this from Lennox-Gastaut syndrome. Patients with Lennox-Gastaut syndrome and EMAS share age of onset (early school age, various kinds of seizures including absences and drop attacks), generalized spike waves, and a major impact on cognitive functions. Thus, the usual understanding, expressed by Aicardi, was that there is a range from Lennox-Gastaut syndrome to myoclonic epilepsy, with myoclonic–astatic epilepsy between these two extremes.¹ This concept of a continuum was similar to that of the Montreal school regarding idiopathic generalized epilepsy (e. g., Berkovic et al.³). However, the concept of a continuum was inconsistent with the idea that one condition was genetically determined, whereas the other resulted from a brain lesion. Some difference should therefore exist. The difficulty in making reliable and reproducible distinctions lies to in the fact that the number of characteristics to be taken in account challenges our ability to identify possible differences. By applying a special mathematical method called “multiple correspondence analysis,”¹⁰ it proved possible to recognize reproducible differences. This method can identify within a group of items belonging to a population those clusters of individuals that differ from the rest of the population for specific items and identify these items.² This method was applied to patients with various types of generalized seizures and various patterns of generalized spike waves, including either 3-Hz spike waves (SW) or slow spike waves (SSW), negative brain imaging, and first seizures between 1 and 10 years of age; two groups could be distinguished:

One group had onset between 5 and 7 years of age had mainly tonic and absence seizures together with SSW, and the course was unfavorable. There was an excess of focal EEG abnormalities. The sex ratio in this group was equal. This is the usual pattern of the Lennox-Gastaut syndrome.

The other group began slightly earlier, between 2 and 5 years of age, with tonic–clonic seizures before the occurrence of myoclonic–astatic seizures and 3-Hz SW. There was an excess of boys. The course was favorable in a majority after 2 or 3 years, although one third had recorded tonic seizures, a feature previously not mentioned in patients who recover. However, in a sizeable proportion, vibratory tonic and absence seizures and long-lasting myoclonic status occurred and the course was unfavorable: Following the disappearance of myoclonic status, clusters of vibratory tonic seizures at the end of night sleep and slow spike waves persisted for years together with major cognitive impact.

Epilepsy with myoclonic–astatic seizures is defined by the combination of myoclonic–astatic seizures and other kinds of generalized seizures, including tonic–clonic, myoclonic, and eventually tonic seizures, absences and erratic myoclonus, and generalized spike-waves beginning in early childhood, between 2 and 5 years of age. The outcome ranges from complete recovery to intractable epilepsy persisting after the end of the second decade and consisting of tonic seizures in sleep with dramatic deterioration of cognitive and motor functions. This syndrome is not related to any brain lesion, but rather to genetic predisposition combined with brain maturational features.

The epidemiology is not known because this condition has long been confused with Lennox-Gastaut syndrome. It is likely that the incidence is at least in the same range as that of Lennox-Gastaut syndrome if not higher.

Although the etiology is unknown, familial studies suggest that some genetic predisposition is at work. However, the variable course has no explanation, and the search for gene mutations has been negative.¹³ The only differences between favorable and unfavorable cases have been with regard to gender, with a poorer prognosis for boys than girls, and the age of onset, with poorer prognosis in case of late onset.¹⁰