INTRODUCTION

The particular epileptic conditions outlined in this chapter are very different from each other. However, they share a similar age of onset and the presence of myoclonia. Both myoclonic absence (MA), and eyelid myoclonia with or without absence (ELMA or ELM), have a highly specific and recognizable video-EEG-polygraphic ictal pattern (if seen once, they will never be confused with other conditions). Moreover, like absence seizures, which can be seen in different epileptic conditions but represent the hallmark of a distinct syndromic entity, namely childhood absence epilepsy (see Chapters 19 and 21), both MA and ELM/ELMA can be observed in different epilepsies but are the distinguishing features of syndromic entities that are labeled by the characteristic seizure type or named Tassinari syndrome and Jeavons syndrome, respectively.

EPILEPSY WITH MYOCLONIC ABSENCES (E-MA, TASSINARI SYNDROME)

General Definitions

The seizure: Myoclonic absences (MAs) were firstly acknowledged as a specific seizure type by Tassinari and coworkers in 1969 (1), through the description of a unique clinical-polygraphic pattern. The recognition of MAs rests on combined video-EEG-polygraphic or polygraphic recording of the ictal event (2–7).

The syndrome: Epilepsy with MA (E-MA) is a rare epilepsy syndrome characterized—as the obvious name suggests—by the occurrence of the hallmark seizure type. It was proposed as a separate entity by Tassinari and Bureau in 1985 (2) and initially included in the ILAE classification of 1989 (8) among the group of cryptogenic or symptomatic generalized epilepsies. In the following proposed ILAE classification (9), E-MA has been classified among the idiopathic epilepsy syndromes of childhood. Finally, in the more recent classifications (10–11), it has been included in the group of childhood epileptic syndromes.

Epidemiology

E-MA is a rare type of epilepsy. The incidence has been found to be 0.5% to 1% in a selected population of epilepsies observed in third referral centers (5). The true incidence of MA seizures is probably higher.

Gender

In contrast to childhood absence epilepsy (CAE), in E-MA there is a male predominance (70%).

Age at Onset

Seizure onset is usually between 3 and 12 years of age (peaking at the age of 7 years). An earlier onset, before 3 years (12–13) or even before 9 months (3,6,14–16), is probably more frequent than reported.

Familial Antecedents of Epilepsy

A family history of epilepsy is reported in about 20% of the cases, mainly idiopathic generalized epilepsy (IGE) (5). Rare cases with consanguineous parents may suggest a possible autosomal recessive mechanism, but a polygenic complex inheritance is more probable. There have been reported cases occurring in siblings (15,17).

Etiology

Myoclonic absence seizures may occur in patients due to a symptomatic epilepsy; for example, related to a pre-perinatal damage or a congenital cerebral palsy (2,5). MAs have been also been observed in patients showing different chromosomal abnormalities such as partial trisomy of the long arm of chromosome 14, Angelman syndrome, 12p trisomy, and inv-dup 15 (3,18–19). Moreover, they have been described in cases with a genetic disorder disrupting SYNGAP1 (20–21), a gene involved in a spectrum of neurodevelopmental disorders associated with intellectual disability and epilepsy (21,22–23).

Finally, more rarely, MAs have been observed in metabolic disorders such as in gain-of-function mutation in glutamate dehydrogenase (24) and GLUT1 deficiency syndrome (25).

Neurological and Developmental Picture at Onset

E-MA occurs in children with a normal neurological and developmental picture in about half of the cases, while the remainder presents with a more or less severe intellectual disability. (7). Neurologic deficits and neuroradiologic abnormalities are present mainly in those with cerebral palsy.

Interictal EEG

The background activity is generally normal. Brief discharges of generalized spike-and-wave and polyspike-and-wave can be recorded in the wake state and during sleep. The evolution of the interictal spike–wave discharges during sleep is similar to that observed in CAE (26). Focal paroxysms generally involving bilaterally the fronto-central regions can be observed in some cases, mainly during slow sleep. Sleep organization is constantly normal and physiologic patterns (vertex spikes, K complex, spindles) are bilaterally present. Photosensitivity is reported only in a few cases (3,15).

Ictal Features

Myoclonic Absences (MAs)

MAs are the defining seizures, constituting the only seizure type in about one-third of the cases. Clinical features include motor and autonomic manifestations, associated with an impairment of consciousness of variable intensity (5). Rhythmic myoclonias, mainly involving proximal upper limb muscles, are the constant features, but typically superimposed on a more or less evident gradual tonic contraction of the same muscles. After each myoclonus, there is a very brief interruption of muscular activity due to postmyoclonic silent period, soon replaced by the reappearance of tonic contraction and subsequent myoclonias (Figures 20.1–20.3). This peculiar and complex muscular activation or inactivation leads to a quite constant and recognizable motor pattern, characterized by a progressive abduction and elevation of the arms with superimposed rhythmic jerking. Myoclonias rarely affect legs or facial muscles. If standing, the subject can show oscillations and/or slight side deviations. Sometimes the myoclonias and the tonic contraction are unilateral or clearly asymmetric despite the generalized EEG pattern (Figure 20.1). The patient often seems to voluntarily grasp his own arms in an attempt to restrain the involuntary jerking, reflecting the usually incomplete loss of awareness. Autonomic manifestations can be associated, consisting of apneas and/or total loss or minor leakage of bladder contents. Ictal EEG shows 3 to 4 Hz spike-and-wave discharge, bilateral, maximal on the anterior head region (apparently comparable to the one observed in “petit mal” typical absences). A phase reversal of the slow waves is observed over frontal leads. The first spike-and-wave complexes are not accompanied by myoclonias, whereas the following complexes are associated to bilateral rhythmic myoclonus—visible on EMG channels—at the same frequency of the spike-and-waves, intruding in the buildup of tonic muscular activity (27). The appearance of myoclonia is related to the progressive increase in amplitude of the downward positive transient of the spike (28) (Figures 20.2–20.3). In fact, on the electromyelogram (EMG), each myoclonus is preceded by the positive spike component, while during the negative or biphasic spike component and the following large slow wave, increasing tonic activity is observed, interrupted by postmyoclonic silent periods of decreasing duration (Figures 20.2–20.4). At times, the spike–wave in the first seconds is of smaller amplitude because the early positive component of the spike is of small amplitude and is not accompanied by myoclonia. The MAs have an abrupt onset and offset. Total seizure duration varies from 6 to 60 seconds. Episodes of MAs usually number in the dozens daily; they are more frequent on awakening and can be elicited by hyperventilation and intermittent photic stimulation (IPS). MAs can also occur during light sleep (Figure 20.4 and 20.5), possibly inducing the patient’s awakening. The status of MAs is rare (3,29), although according to Bureau and Tassinari (5) absence status without myoclonias occurred in 17% of their cases.

FIGURE 20.1 Myoclonic absence characterized by a 3 Hz spike-and-waves discharge lasting 10 seconds. The rhythmic jerks appear 2 seconds after onset of the spike–wave discharge. Note that both myoclonic jerks and tonic contraction are asymmetrically predominant.

FIGURE 20.2 Myoclonic absence characterized by a 3 Hz polyspike and waves related with rhythmic jerks synchronous on both deltoids. Note the increasing tonic component fragmented by the postmyoclonic silent period. The myoclonias appear 1 second after onset of the EEG discharges when the downward positive transient of the spike increases in amplitude.

Other Seizure Types

Other seizure types are present in the majority of patients, being mainly generalized tonic–clonic seizures (GTCS), these occurring before MA or concomitantly. Also, “drop” seizures (either tonic or atonic) or atypical absences (without myoclonias) can take place. The appearance of seizure types other than MA can suggest the outcome. In fact, patients in whom MAs are associated only with atypical absences have a better prognosis in terms of seizure freedom than do subjects experiencing GTCS (5,15,30). Appearance of tonic seizures associated with fast activity can herald evolution toward a Lennox–Gastaut syndrome (LGS).

FIGURE 20.3 Schematic view of the relationship between spike-and-wave and muscular activity. Each myoclonia is preceded by the deep positive downward transient (dotted segment) of the spike (A). The increasing tonic activity is interrupted by postmyoclonic silent periods of decreasing duration (B).

Treatment

Valproate alone (16,31) or mainly associated with ethosuximide, with appropriate daily doses and plasma levels, is the more efficient treatment, particularly if MAs are not associated with other seizure types (3,5,30,32). Manonmani and Wallace (15) observed that the association of valproate or ethosuximide with lamotrigine could have a favorable effect in resistant cases. Hausler et al (33) reported some good results with the association of rufinamide. In different cases, the addition of phenobarbital or benzodiazepines to valproate can lead to good control of seizures, while such antiepileptic drugs (AEDs) as phenytoin, vigabatrin, and carbamazepine may aggravate seizures, even if Manonmani and Wallace (15) reported an unexpected optimal result with carbamazepine in one subject.

The experience with levetiracetam, topiramate, and zonisamide is limited (7).

Evolution

A longitudinal study of long-term prognosis performed on the 42 cases of the Centre Saint Paul in Marseille (4) shows that MAs disappear in 38% of cases and that they persist or the epilepsy changes in the other 62%. In the latter cases, the MAs persist, being associated or not with other seizure types, or eventually only other seizure types can persist after the disappearance of MAs. In particular, an evolution into LGS is possible, mostly when tonic seizures complicate the picture. During the long-term evolution, after the “stage” of LGS, focal seizures can appear, with clinical features suggestive for an early involvement of supplementary motor area (27). According to some authors (4,30,34), the evolution of epilepsy seems to be worst in the presence of associated GTCS, although the prognostic value of an early adequate treatment remains debatable. Cognitive impairment and particularly learning problems are reported in 70% of cases (4,6,15). A good evolution is possible even in cases with an early onset, mainly in cases without obvious cognitive and neurological deficits at onset (16,32).

Pathophysiology

The epileptic network involved in MA generation can be hypothesized indirectly, based on the fact that this peculiar type of seizure can be viewed as an overlap of three different components (and the respective generating network) (27): the “typical absences,” suggesting the involvement of cortico-thalamic circuit; the surface-positive spike component, related to rhythmic myoclonias, arising from the motor area involvement; and the possible involvement of frontal cortex; particularly supplementary motor area (35) and brainstem generating the “tonic seizure.” The prominence of the involvement of this latter circuit—evidenced by the exacerbation of tonic seizures—may reveal a negative prognostic value.

EPILEPSY WITH EYELID MYOCLONIA AND ABSENCES (E-ELMA, JEAVONS SYNDROME)

General Definitions

First described as a separate kind of myoclonic epilepsy by Jeavons in 1977 (36), in the following decades, this entity has been recognized by several authors as a unique electroclinical syndrome (37–48).

In his original description, Jeavons strongly emphasized the ictal phenomenon and its link with sensitivity to eye closure and photic stimulation: “Eyelid myoclonia and absences show a marked jerking of the eyelids immediately after eye closure and there is an associated brief spike and wave activity. The eyelid movement is like rapid blinking and the eyes deviate upwards, in contrast to the very slight flicker of eyelids which may be seen in a typical absence in which the eyes look straight ahead. Brief absences may occur spontaneously and are accompanied by 3 cycles per second spike and wave discharges. The spike and wave discharge seen immediately after eye closure does not occur in the dark. Their presence in the routine EEG is a very reliable warning that abnormality will be evoked by photic stimulation” (36). Since then, the epilepsy with eyelid myoclonia and absences (E-ELMA) has been alternatively named Jeavons syndrome. However, it should be borne in mind that the distinctive feature of Jeavons syndrome, namely the eyelid myoclonia (ELM), can be observed also in different epilepsies, such as juvenile myoclonic epilepsy (JME) or Janz syndrome. In fact, the equivalence of ELM and Jeavons syndrome should be avoided, the first being a specific seizure type necessary—but not sufficient—to diagnose the syndrome, for which the presence of the triad of (1) eyelid myoclonia, (2) eye-closure sensitivity, and (3) photosensitivity (42) is required. Eye-closure sensitivity (ECS) is defined as an abnormal response to the act of closing the eyes, being thus a special type of visual sensitivity, characterized by the occurrence of absence seizures and/or EEG paroxysmal activity within 0.5 to 4 seconds after eye closure (see the section on ictal features). Photosensitivity is represented by the occurrence of epileptiform abnormalities or seizures induced by IPS to configure the so-called photo-paroxysmal response (PPR). Absences in Jeavons syndrome may occur independently of eye closure and even not associated with marked eyelid jerking (eg, during hyperventilation); thus, the term “eyelid myoclonia and absences” has been considered more appropriate than the term “eyelid myoclonia with absences” (48).

FIGURE 20.4 Same subject as in Figure 20.2. Myoclonic absence during sleep phase II. Note the significant increase of the tonic component and the presence of the interictal slow spikes on the vertex and frontal regions.

FIGURE 20.5 Myoclonic absence recurring while the awake and during sleep. Note that during sleep stage II and slow sleep the myoclonic absences became progressively briefer.

Epidemiology

The prevalence of E-ELMA has been reported to range between 7.3% and 12.9% in all adult patients with idiopathic generalized epilepsies (38,42–44), in which about 2.6% of all patients have epileptic disorders (42,44). A lower prevalence, respectively, of 2.7% and 0.56% has been reported in the pediatric population by Caraballo et al (45).

Gender

Female gender predominates, ranging between 60% (45) and 80% (44) of all cases.

Age at Onset

The age at onset ranges between 2 and 14 years, with a peak at 6 to 8 years (42–45,49). It must be considered that in many cases the diagnosis may be delayed even for years (50) because ELM can be overlooked or mistaken for facial tics or mannerisms (43,51). However, in the majority of cases, a prompt diagnosis can be obtained through a good clinical history taking accompanied by a routine EEG (52), although video-EEG-recordings are more informative.

Familial Antecedents of Epilepsy

A family history of epilepsy is reported in 28% (44) to 39.5% (45) of the cases. Among those, there are a certain number of first-degree relatives with E-ELMA or IGE, supporting a dominant mode of inheritance in some familial cases (44,53–57). However, in a greater number of subjects, a complex inheritance has been reported with shared genetic determinants overlapping with “classical” IGE and GEFS+ (58). In this probable complex multigenic inheritance, one gene among others deserves mention; in fact, the CHD2 gene has been suggested to be linked to both photosensitivity and self-induced seizures (22,59). Moreover, recent data suggest CHD2 as an important contributor for the occurrence of eyelid myoclonia seizure and Jeavons syndrome (60).

Neurological and Developmental Picture at Onset

All subjects are neurologically normal at onset. Cognitive and developmental aspects are reported to be normal at onset even in the subgroup of patients with subsequent impaired intellectual functions (45,52,61). However, it can be difficult, particularly in subjects with an early onset (namely, before 3 years of age), to exclude some preexisting neuropsychologic defects.

Interictal EEG

The background EEG activity is normal in the majority of the cases both in wakefulness and sleep. In some subjects having intellectual disability, it is possible to observe an excess of slow–wave activity (45,62). The interictal EEG shows isolated generalized spike or polyspike and wave discharges predominating in the anterior or posterior regions while awake. They are generally activated by hyperventilation, drowsiness, and sleep. Intermittent photic stimulation is always positive. In some patients, it is also possible to recognize focal abnormalities involving central or parieto-occipital regions. In a significant number of patients, it is possible to observe a “spiky” appearance of posterior alpha rhythm after eye closure, dissimilar from both the “squeak phenomenon” in normal subjects and from focal posterior epileptiform discharges observed in fixation-off sensitivity (63).

Ictal Features

Eyelid Myoclonia (ELM) or Eyelid Myoclonia and Absences (ELMA)

Two different ictal patterns can be observed, usually triggered by eye closure or photic stimulation: (1) a very brief (a few tens or hundreds of milliseconds) fast activity discharge, predominating in fronto-central or parieto-occipital regions, associated with eyelid flickering without upward eye deviation and without associated “absence” (Figure 20.6); and (2) a diffuse 3 to 5 Hz polyspike-and-wave discharge lasting 2 to 6 seconds, often irregular and fragmented, associated with eyelid myoclonias, upward eyeball deviation, sometimes with retropulsion of the head (Figure 20.7). This latter pattern can be isolated, repetitive, or followed by a generalized discharge associated with a more or less obvious loss of awareness/responsiveness (absence). If eyelid jerking is marked, the subject becomes unable to voluntarily control eye movements. Thus, there is a sequence of eyes opening/eyes closure that induces the recurrence/maintenance of the ictal manifestation for seconds before the subjects regain the ability to control their eyes, so that with eyes open the EEG and clinical picture return to normal baseline state. Both patterns occur immediately (within 0.5–4 seconds) after eye closure in an illuminated recording room and are usually not evoked in total darkness, even if exceptions exist (64).

FIGURE 20.6 Neurologically and intellectually normal female having untreated eyelid myoclonias since the age of 7 years and one partial occipital seizure induced by IPS stimulation at the age of 11. Note the brief, very fast diffuse polyspikes discharges predominating on the frontal region related to eyelid flickering (black dots). The seizures are both spontaneous and triggered by IPS.

Myoclonic jerks, other than eyelid, are rarely reported during ELM or ELMA (44), affecting limbs and usually occurring in a random fashion (65), without constituting a different type of seizure (see section on “Other Seizure Types”).

FIGURE 20.7 Normally developing boys of 5 years 7 months starting to have very frequent eyelid myoclonias with absences since the age of 5 years. Note the diffuse discharges of polyspikes and waves in brief bursts lasting around 3 seconds, associated with eyelid myoclonias, eyeballs-upward deviation, and absence.

Eyelid myoclonia is not only the most distinctive feature of Jeavons syndrome, but also the most pervasive and drug-resistant one, persisting into adulthood, even without apparent absences or demonstrable photosensitivity, and both of the latter decreasing with age (42).

Status Epilepticus

A nonconvulsive ELMA status epilepticus, even if relatively rare (about 5% in the series described by Caraballo and coworkers (45)), has been reported by several authors (57,61,64,66–71). The incidence of this status seems to be more elevated (up to 72%) in subjects with intellectual disability (61). This “ELMA status” is characterized by a subcontinuous diffuse fast polyspike–wave discharge on EEG, clinically associated with ELM and obtundation state of varying degree (sometimes very subtle and difficult to recognize, particularly in intellectually deficient patients) (Figure 20.8). The ELMA status can last from one to several hours and can recur sporadically or very frequently. It can be elicited by photic stimulation, but usually it appears spontaneously, particularly on waking up in the morning. During the status, very fast myoclonic jerks involving the arms concomitant with eyelid myoclonias can occur in brief clusters (Figure 20.9).

Self-Induction

Self-induction of ELMA is relatively frequent (9.5%), being more rare in subjects with normal neurocognitive picture but frequent in patients with associated intellectual disability; respectively 3.7% and 44% of subjects, according to Caraballo et al (45). It is still debated whether the repeated eye blinking while staring at a television or toward the sun observed in some patients is a deliberate attempt at self-induction or an ictal phenomenon (45,48,72). Patients may also not be deliberate self-inducers; instead, they may suffer from compulsive self-induction, similar to the phenomenology described in Tourette syndrome (73). In a few cases, the patients admit the compulsive self-induction in search of a pleasant though ill-defined sensation occurring during the ELMA. This phenomenon is more frequent (but not exclusive) in patients with intellectual disability, in which it can be observed particularly during periods of boredom, probably sharing some mechanism with stereotypies. Some of the patients will eventually continue to show slight flutter of the eyelids on eye closure, as a habit, without associated EEG discharges (70).

Other Seizure Types

Absence Seizures

Absences associated with generalized spike–wave discharges (SWD) occurring independently of eye closure are rarely reported during hyperventilation and IPS. In fact, it is very difficult to ascertain that they are really not an ECS phenomenon. Typical absences are not seen or are very rare (74).

Myoclonic Seizures (other than ELM/ELMA)

Myoclonic seizures different from ELM/ELMA are reported with a variable frequency by different authors [16% Caraballo (45); 34% Covanis (70); 54.5% (42)]. They can occur either independently or in association with eyelid jerking upon eye closure, in the latter case being the distinction from the controversial ELM/ELMA (partly justifying the variability in the frequency estimation). The jerks usually involve the neck/head or upper part of the body, but they can also involve the legs, inducing a sudden drop. Myoclonic jerks can be symmetric but also asymmetric; they frequently occur in clusters on awakening, and are usually elicited by sleep deprivation and IPS. The dissimilar reported incidence probably depend on the inclusion criteria used by different authors and on the age of the patients at the time of observation. In fact, in some cases, myoclonic seizures appear before the onset of ELM in the context of a myoclonic epilepsy of infancy (40,75–77). In some of these cases, myoclonic seizures may reappear later in the evolution, associated or not to eyelid myoclonias. In other patients, massive myoclonias appear through the follow-up of “classic” ELMA patients. Lastly, in some patients, these myoclonic seizures persist as the only seizure type, after the disappearance of ELM/ELMA (45).

FIGURE 20.8 9 years 5 month old female with mild intellectual disability starting to have ELMA recognized since the age of 3 years and presenting, since the age of 4, frequent “ELMA status” lasting from 30 minutes to several hours. Note the subcontinuous very fast polyspike discharges elicited by eye closure.

FIGURE 20.9 Same subject and recording as in Figure 20.7. Note as during status at time, the eyelid myoclonias are associated with brief bursts of rhythmic jerks involving both deltoids.

Generalized Tonic–Clonic Seizures (GTCS)

According to Covanis (44), GTCS occur in about half of unsuccessfully treated or untreated patients. In the latter condition, usually the reason for referral is in the context of a “mild” form with ELM, since then unnoticed. Caraballo and coworkers (45) report a higher incidence of GTCS (69%). Again, differences in incidence vary accordingly to clinical features of the patients analyzed, as well documented by Caraballo et al (45). In their study population, spontaneous GTCS was present in about 46% of patients without cognitive impairment, whereas GTCS were only induced by IPS or by watching television or video games in another 17% of subjects. On the contrary, all subjects with intellectual disability experienced GTCS. Along the same lines, Capovilla and coworkers (61) found a GTCS incidence of 77% in their selected population with impaired intellectual function.

Focal Seizures

Occasionally, focal seizures can be observed, particularly with onset in occipital regions, and possibly induced by photic stimulation.

According to age at onset and seizure semiology, Covanis et al (31,44,48) propose the following classification (note that Covanis’s use of “ELMA” corresponds to our “E-ELMA”):

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