In this chapter, we review two well-individualized early-onset myoclonic epilepsies included in the category of genetic generalized epilepsies in the 2010 International League Against Epilepsy (ILAE) organization scheme (1): myoclonic epilepsy in infancy (MEI) and epilepsy with myoclonic atonic seizures (EMAS), or Doose syndrome (DS). The characteristic traits of these two epilepsy syndromes are summarized in Table 17.1.

MYOCLONIC EPILEPSY IN INFANCY

Introduction and Definition

Myoclonic epilepsy in infancy was individualized among the early-onset myoclonic epilepsies nearly 30 years ago (2). MEI stands out as the earliest form of genetic generalized epilepsy (3,4). It is easily recognizable, with solid clinical and electroencephalographic features. Extensive experience with this syndrome has led to the description of clinical variants, which share an excellent overall prognosis in most patients. Its diagnostic criteria can be summarized as follows:

Epidemiology

In our experience, MEI is uncommon, and boys clearly outnumber girls (M/F ratio close to 2). MEI represents less than 1% of all epilepsies and less than 2% of all genetic generalized epilepsies (5). This was confirmed by other studies, with MEI representing around 2% of all epilepsies with onset in the first 3 years of life (6), or 1% to 2% of all epilepsies with onset in the first year of life (7,8).

Clinical Manifestations

Myoclonic jerks usually begin between the ages of 4 months and 3 years. At the onset, clinical manifestations are usually subtle (rare myoclonias seen less often than once a day). After a few weeks or months, they become more frequent and more obvious. Myoclonias prominently involve the upper limbs, with a sudden upward extension, are usually bilateral, and may be associated with a head drop and a quick upward deviation of the eyes. They may cause falls, drops of objects, or crying. If a short cluster occurs, it does not last more than 2 to 3 seconds. Absence seizures have been noted in up to 20% of patients (9). Sudden brief vocalization (10), or longer myoclonic attacks lasting up to 5 seconds (11), have also been reported, but are uncommon. There are usually no specific triggering factors, and attacks occur unexpectedly (although a slight increase of frequency may be noted during drowsiness in some children).

A significant clinical variant, described as reflex MEI (12,13,14), is characterized by the triggering of myoclonic jerks by sudden tactile or acoustic stimuli. Its prognosis does not differ from the usual type, and it may even be more benign (15,16). Certain authors have stressed the possibility of a later age at onset, but such patients still experience the self-limited course of the usual type of MEI. There is no apparent overlap with juvenile myoclonic epilepsy (JME) (17). Recently, a series of patients with nocturnal myoclonias only has been reported, and this has been considered as another clinical variant by the authors (18).

TABLE 17.1

There are no significant associated features. Cognitive development and behavior remain normal in most, although certain patients may experience various problems in this respect. A recent study showed that attention deficit or IQ slightly below normal can be found in single cases (19), but the significance of such findings is disputable (5).

EEG Features

MEI is not associated with important global changes of the background awake or sleep EEG (Figure 17.1). The interictal EEG is normal, with the exception of rare generalized discharges not associated with myoclonias that can be observed occasionally, especially during sleep. Most importantly, all myoclonias occur in association with EEG discharges. The EEG may remain fully normal if no myoclonic attacks are recorded, and so long-term waking video-EEGs should be obtained until the ictal event is well documented. Sleep EEGs are useful in terms of differential diagnosis, because most other syndromes that may be suspected in the early diagnostic phases are associated with significant global EEG changes during sleep or at awakening. However, drowsiness may in some cases increase the incidence of jerks, and it is recommended that a daytime sleep recording (easy to obtain in infants or very young children) be added to the clinical workup of these patients.

The typical EEG feature is a brief discharge of irregular, often fast, spike–waves or polyspike–waves that is very often associated with myoclonic jerks (Figure 17.1). This discharge can predominate anteriorly. Myoclonic jerks occur as an isolated event, or in very brief rhythmic or near-rhythmic clusters of 2–4 jerks, and may be associated with brief loss of tone in axial muscles (neck).

The reflex form typically appears slightly later, after infancy. The jerks may begin in the eyelids, but they predominate in the arms in most patients (12). A photoparoxysmal response following intermittent photic stimulation (IPS) may be found in approximately 10% of patients, sometimes inducing myoclonic jerks (5,17,20,21). Focal changes, mostly in the form of frontal or temporal spike–waves, can be found transiently in rare cases, often only in sleep recordings (5,20).

Pathophysiology

The only significant personal history in patients with MEI is the occurrence of simple febrile seizures, which precede (or coexist with) MEI in up to 26% of cases (5). The main pathophysiological discussions surrounding benign myoclonic epilepsy in infancy (BMEI) concern the genetic context. Indeed, a family history of epilepsy (mostly genetic generalized) and/or febrile seizures is present in up to 44% of cases. There is no report of familial cases of MEI, but this condition may occur in association with other forms of epilepsy in some families. One patient had a sibling with myoclonic–astatic epilepsy (22), but other family histories have not been reported in detail. There is, at present, no data to formally link MEI with other myoclonic epilepsies or to a larger grouping of genetic epilepsies, nor is there data to exclude such linkage. The genetic factors suspected to underlie this syndrome remain to be discovered.

FIGURE 17.1 Myoclonic epilepsy in infancy (MEI). Two-year old female infant with onset before age 1 of myoclonic jerks, who remained untreated until this polygraphic-EEG evaluation at age 2, showing waking and drowsiness. Note the correlation between generalized, irregular spike–wave discharges on the EEG and myoclonic jerks shown on the deltoid EMG leads.

Diagnostic Evaluation and Differential Diagnosis

The diagnosis of MEI should immediately come to mind when myoclonic jerks occur in an infant who is developing normally. The only major differential diagnosis in this age class is with benign infantile spasms (23), a comparatively frequent, likewise benign condition in which the clinical manifestations occur in clusters and in which the interictal and ictal EEG remains normal. A familial infantile myoclonic epilepsy was reported in a large family, with benign outcome and autosomal recessive inheritance and clinical and EEG characteristics that differ from both BMEI and severe myoclonic epilepsy of infancy (SMEI) (24). These patients often had long-lasting myoclonic attacks preceding GTCS; the GTCS were the initial seizure type in most, and seizures tended to persist into adulthood. Febrile myoclonus is clearly a different entity (25).

The diagnosis of MEI is easily confirmed by video-EEG monitoring. Video documentation of the attacks by the family may be of help at the first consultation and should be requested whenever possible. The frequency of myoclonic jerks is usually such that video-EEG monitoring, coupled with polygraphic recording of the jerks by surface EMG, is productive (Figure 17.1). However, several hours of recording, or repeated recordings, may be necessary in some cases. In the absence of clear video or polygraphic data, or in the presence of atypical findings, the diagnosis and prognosis should remain open; long-term follow-up is necessary to secure a diagnosis in such patients. Neuroimaging procedures are seldom performed and do not reveal significant findings (5). Cognitive and behavioral assessment may be useful for the management of cases with problems in these areas.

Treatment

Myoclonic jerks are easily controlled by valproate (5). Untreated patients continue to experience myoclonic attacks, and this may contribute to difficulties in terms of psychomotor development and behavior. Thus, the classically recommended action is to treat patients with valproate and try to discontinue treatment after 2 years of seizure freedom.

In their review of the literature, Dravet and Bureau (5) stressed the major efficacy of valproate in MEI. Out of 87 patients treated in monotherapy, 73 of 82 became seizure free on valproate, 2 of 2 on phenobarbital, and 2 of 2 on clonazepam. The addition of phenobarbital, clonazepam, or clobazam resulted in seizure freedom in half of those who had not responded to valproate. Overall, 94% of the patients become seizure free on therapy. Resistance to valproate may be overcome using high initial doses (30 to 40 mg/kg) (10). There are also patients with a very benign course who remained untreated; the necessity of drug treatment should be discussed on an individual basis.

Course and Prognosis

In most cases, MEI is a self-limited condition, with an active period seldom lasting more than a few years, and with spontaneous remission during childhood. Myoclonic jerks disappear after a period of active epilepsy that may be shortened by anticonvulsant treatment; intellectual development progresses normally, and the EEG normalizes. However, this rule does not apply to all patients. Persistence of myoclonic attacks may lead to impaired psychomotor development and behavioral disturbances (5,26). Cases with reflex myoclonic jerks appear to have a more benign course, and often do not necessitate treatment.

In most patients, no other seizure types than myoclonias are seen during the course of MEI, with the exception of occasional simple febrile seizures, absences (11), and afebrile GTCS: the latter occur very late, usually during adolescence, and are often ascribed to drug withdrawal at that age. Valproate may still be withdrawn without recurrence of GTCS in some, but has to be maintained in others, for example, because of persisting photosensitivity. Photosensitivity can indeed appear after the cessation of myoclonic jerks and may persist into adulthood (10,27,28). A multicenter study reported that, among 34 MEI patients diagnosed between 1981 and 2002, two later developed JME (29). Additional patients developed other epilepsy syndromes later on, such as epilepsy with myoclonic atonic seizures (30), childhood absence epilepsy (31), or Jeavons syndrome (32). Such findings remain exceptional.

The cognitive outcome of MEI is a matter of debate (5,33). On long-term follow-up, up to a third of patients (34) have cognitive difficulties. As mentioned earlier, those with reflex-triggered seizures seem to have a more favorable outcome than those with the “classic” form of the syndrome (13,34). The pathogenesis of such unfavorable outcomes is probably multifactorial. In addition to the existence of comorbidities, it appears that treatment delay (in patients with frequent attacks), familial anxiety, and inappropriate educational attitudes, as well as underlying putative biological factors, may contribute to a less than fully favorable prognosis in some patients; hence the proposal of the ILAE to abandon the term benign, previously appended to that epilepsy syndrome, in 2010 (1).

EPILEPSY WITH MYOCLONIC–ATONIC SEIZURES (DOOSE SYNDROME)

Introduction and Definition

EMAS is one of the few epileptic syndromes named after a particular seizure type (35). It is also known under the name of Doose syndrome, a tribute to Hermann Doose, the author who first described it as “akinetic petit mal” (36) and then “centrencephalic myoclonic-astatic petit mal” 50 years ago (37). EMAS was classified among the cryptogenic or symptomatic generalized epilepsies in the 1989 international classification of epilepsies (3), but rightly moved to the idiopathic category in the 2001 proposal (4), now renamed genetic (1).

The diagnostic criteria of EMAS can be summarized as follows:

Epidemiology

The sex ratio cants strongly toward males (2.7–3:1) (38). Incidence data vary according to the precise definition used, but overall EMAS represents 1% to 2% of all childhood epilepsies (39), or 2.2% of children with seizure onset between age 1 and 10 years in a hospital-based study (40).

Clinical Manifestations

EMAS occurs in neurologically normal young children. Seizure onset is between 18 and 60 months, and 94% of the children start their seizures before age 5 years. Onset in children older than 7 has not been reported. EMAS may be preceded by (or associated with) simple febrile seizures in 11% to 28% of children in the usual age range (age 17–40 months) (40,41), or 90% if EMAS occurs in genetic epilepsy with febrile seizures+ (GEFS+) families (42).

The first seizures are usually generalized tonic–clonic, but soon after, they become myoclonic. They increase in frequency over a few months (43). Up to one-third of patients can experience, within 1 to 3 months, a “stormy” evolution with multiple convulsive seizures per day, episodes of nonconvulsive status, or multiple daily falls due to myoclonic–atonic seizures (38). Such patients do not necessarily have a worse outcome than those with a more gradual onset.

The characteristic presentation of EMAS is as a multiple seizure disorder. Myoclonic and myoclonic–atonic seizures are present in all, as are generalized jerks occurring isolated or in clusters of 2 to 3. A prominent feature consists of sudden falls that may be related to myoclonic jerks or to atonia, usually to a combination of both. This can be documented by polygraphic video-EEG recording (44). Injuries are common. Minor episodes are limited to head drops.

The following seizure types may occur in EMAS (38,40,41):

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