INTRODUCTION

The subgroup of generalized epilepsies which previously was known as idiopathic is now suggested to be termed genetic (1). These changes are part of those proposed by the ILAE Commission on Classification and Terminology 2005–2009, which replaced the well-established 1989 International Classification of Epileptic Syndromes and Epilepsies (2). The proposal regarding a revision of the classification and terminology of epileptic seizures and epilepsy up to this point has not been approved by the ILAE, and controversial discussion including the use of the etiologic terms idiopathic vs. genetic is still prevalent (3,4). Beyond terminology, however, the conceptual considerations are very similar. Genetic epilepsy is, “as best as understood, the direct result of a known or presumed genetic defect in which seizures are the core symptom of the disorder” (1).

Prevalence studies consistently demonstrate that genetic generalized epilepsies (GGE) make up 15% to 20% of all epilepsies (5–7). Subsyndromes of GGE that also qualify for the newly proposed category of “electroclinical syndromes” (1) are characterized and defined by age at onset of epilepsy, by the predominant seizure type, and maybe by long-term seizure outcome. Three GGE subsyndromes commonly commence in adolescence, that is, between the ages of 12 and 18 years (Figure 21.1). These comprise juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal only either manifesting on awakening (EGMA) or by random (EGMR), all of which are covered in the current chapter.

Though these subsyndromes may overlap within the group of patients with GGE and may evolve from one to another in individual patients, in the following text, clinical and EEG characteristics as well as prognostic features are discussed separately for each clinical form. For the genetic and pathophysiologic basis of GEE, including those with adolescent onset, readers are referred to the chapters of Section 1, “Basic Mechanisms.”

JUVENILE ABSENCE EPILEPSY

Epidemiology

Population-based epidemiologic studies may give detailed prevalence data on GGE as a whole group, but not on subsyndromes such as juvenile absence epilepsy (JAE). It has been estimated that approximately 10% to 15% of patients with GGE suffer from JAE (9,10). Sex distribution has been reported to be equal (10,11). The condition seems to be less frequent than childhood absence epilepsy (CAE), but bears the risk of being underdiagnosed and thus underreported as long as absence seizures are the only seizure type that in contrast to CAE, manifests rather sporadically.

Definition and Clinical Features

The definition of JAE as given by the 1989 International Classification of Epileptic Syndromes and Epilepsies is rather a description: “The absences of juvenile absence epilepsy are the same as in pyknolepsy [= CAE, the author], but absences with retropulsive movements are less common. Manifestation occurs around puberty. Seizure frequency is lower than in pyknolepsy, with absences occurring less frequently than every day, mostly sporadically. Association with GTCS [= generalized tonic-clonic seizure, the author] is frequent, and GTCS precede the absence manifestations more often than in childhood absence epilepsy, often occurring on awakening. Not infrequently, the patients also have myoclonic seizures. Sex distribution is equal. The spike-waves are often >3 Hz. Response to therapy is excellent” (2).

Due to a lack of strict criteria, this definition makes delineation of JAE from CAE difficult. In a cohort of patients with absence epilepsies initially treated and diagnosed by Dieter Janz (Berlin, Germany), we related age at onset of absence seizures to a pyknoleptic (>1 seizure per day) or nonpyknoleptic course. We observed that 78% of 109 patients had “pure subsyndromes” with either absence seizure onset at age 10 years or younger and pyknoleptic absences (CAE, 49%) or seizure onset beyond 10 years of age and non-pyknoleptic absences (JAE, 29%). However, there was an overlapping group not fitting these criteria amounting to 22% of patients with absence seizures confirming previous findings (11) (Figure 21.2).

FIGURE 21.1 Schematic ranges and peaks of manifestation of childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal on awakening (EGMA).

Source: Adapted with permission from Ref. (8). Janz D. Epilepsy with grand mal on awakening and sleep-waking cycle. Clin Neurophysiol. 2000;111(Suppl 2):S103–S110.

In a detailed video-EEG study on 224 typical absence seizures in 20 patients, Panayiotopoulos reported that absence seizures in JAE are accompanied by less severe impairment of consciousness compared to CAE; in addition, automatisms occurred in both groups and were correlated to the severity of impaired consciousness (12). In that study, opening of the eyes was observed in all absence seizures in CAE but only in half of those in JAE. No further semiologic differences were described.

In JAE, the majority of patients—in addition to absence seizures—suffer from GTCS, which often manifests on awakening. In an Austrian study comparing 64 patients with JAE and CAE, 95% of JAE patients and 69% with CAE had GTCS (11). In our cohort of patients described earlier with absence epilepsy, the median manifestation of GTCS was 4 years after that of absence seizures (r = 0.023; P = .011). In every fifth patient with JAE, epilepsy manifested with GTSC. However, both studies rely on a prevalence cohort; patients were recruited in adult epilepsy centers, and therefore were likely to represent a subgroup with a rather unfavorable course. The prevalence rate of GTCS in all patients with JAE seems to be slightly lower.

EEG

Ictal generalized EEG discharges with spike–wave morphology occur at a frequency of 3 to 4/sec; EEG background activity is generally normal (≥ 8 Hz) (Figure 21.3). In the video-EEG study by Panayiotopoulos, ictal discharges in JAE lasted a mean of 16 sec, and thus were longer than those in CAE (12 sec) (12). In JAE as compared to CAE, spike–wave discharges display a slightly higher frequency and are more often disorganized (13). Whether generalized discharges are a reflection of an absence seizure or represent an interictal condition depends on the presence of impaired consciousness or other cognitive functions.

FIGURE 21.2 Distribution of age at seizure onset in patients with pyknoleptic absence seizures (gray bars) and nonpyknoleptic absence seizures (black bars). PA, pyknoleptic absence seizures; NPA, nonpynkoleptic absence seizures.

Source: Adapted with permission from Ref. (11). Trinka E, Baumgartner S, Unterberger I, et al. Long-term prognosis for childhood and juvenile absence epilepsy. J Neurol. 2004;251:1235–1241.

FIGURE 21.3 A 14-year-old boy with juvenile absence epilepsy for 2 years. One year ago, the patient suffered the first generalized tonic–clonic seizure (GTCS); since then, five GTCS have occurred. Absence seizures occur twice per week, despite treatment with ethosuximide at 1,000 mg and lamotrigine at 300 mg daily. Ictal EEG shows the pattern of a typical absence seizure with generalized spike–wave discharges, which at onset had a frequency of 4 to 5/sec. In the further course, discharge frequency declines to 3/sec, and duration of the absence seizure and corresponding EEG discharges is 16 sec. Semiologically, the seizure is characterized by loss of contact with the environment without overt motor signs.

One study reported an increased frequency of temporal intermittent rhythmic delta activity (TIRDA) in patients with JAE, which was not seen in other GGE with adolescent onset (14). However, TIRDA occurred in only 13% of JAE patients, which is too low a frequency rate to serve as a reliable biologic marker.

Treatment

While anti-ictal pharmacologic treatment has been assessed in a randomized controlled trial in CAE (15), unfortunately no such monotherapy data is specifically available for JAE. However, it is likely that ethosuximide and valproic acid, which have been more successful than lamotrigine in CAE, may also be efficacious in controlling absence seizures in JAE. Wolf and Inoue have reported the treatment response in 223 adolescent and adult patients with absence epilepsy who were still treated in an adult epilepsy outpatient clinic, indicating a more difficult-to-treat course of epilepsy (16). However, even in this group, treatment response was excellent, and 82% of patients—the majority of whom were treated with ethosuximide and/or valproic—were free of absence seizures for at least 1 year. Lifetime occurrence of more than 10 GTCS was a predictor for treatment failure.

In cases of intractable JAE, add-on levetiracetam resulted in a median reduction of seizure frequency of 66% compared to 25% with placebo (17). In 13 adult patients (mean age 42 years; seven had GTCS in the last 12 months), treatment with zonisamide resulted in seizure freedom in five patients, seizure frequency reduction between 75% and 99% in three patients, and seizure frequency reduction between 50% and 74% in another five patients (18). Similar to ethosuximide, zonisamide inactivates T-type Ca⁺⁺ channels (19), which play a major role in the thalamo-cortical circuit generating absence seizures (20).

Some anti-ictal substances such as carbamazepine, oxcarbazepine, and phenytoin, which are highly efficacious in partial epilepsy, may have detrimental effects in GGE such as JAE by aggravating absence seizures (21,22).

Prognosis

Long-term seizure outcome data are not available from prospectively followed incidence cohorts, but only from retrospective prevalence cohorts.

A Czech study reported 46 JAE patients with a mean age of 31 years and a mean duration of epilepsy of 18 years. In the terminal 5 years, only seven patients were completely seizure free (15%), eight had absence seizures only (18%), but 31 had at least one GTCS with or without additional absence seizures (67%) (23). All patients were still on anti-ictal pharmacologic treatment, with 20 on mono- and 26 on polytherapy. This rather unfavorable seizure outcome may be due to the population studied, which consisted of patients who had been transferred to a specialized epilepsy center for treatment. The negative bias of prevalence cohorts of JAE patients on prognosis has been discussed earlier.

In the Austrian study mentioned earlier, 64 JAE patients had a follow-up of 22 years, 37% were seizure free in the terminal 2 years, and the vast majority were still treated anti-ictally (11). A meta-analysis on CAE and JAE with 27% of patients being adolescents or adults at absence epilepsy onset revealed terminal seizure freedom (duration depended on the time of follow-up, which was heterogeneous) in 59% of patients (24). Absence epilepsies without GTCS had a more favorable outcome (78% seizure free) than those with GTCS (35%). Another predictor for long-term seizure freedom in absence epilepsies was older age; the older the patients were and hence the longer epilepsy would have lasted, the less likely they still had seizures. Though this meta-analysis mixed up CAE and JAE, other studies support the finding that lack of GTCS and older age predict a favorable prognosis in JAE.

Reliable long-term seizure outcome data on the whole group of JAE patients are currently not available; however, they are probably better than suggested in the previously mentioned retrospective studies, and they can only be derived from future prospective studies or registers.

JUVENILE MYOCLONIC EPILEPSY

Epidemiology

In a population-based incidence study on new-onset epilepsy in Nova Scotia, Canada, 24 out of 692 children and adolescents were diagnosed with juvenile myoclonic epilepsy (JME; 3.5%) (25). This rather low prevalence rate may in part be explained by the fact that patients were only included until the age of 16 years; thus, patients with later manifestation were missed. In an adult epilepsy center, prevalence of JME was 9.2% among all 2,190 patients and 45.5% among those with GGE (10). Other data support the finding that JME is the most common GGE subsyndrome, which makes up 10% to 11% of all epilepsies (26,27). While earlier studies report an equal sex distribution (9), in the majority of series, there is clear female preponderance of 65% to 75% in the rate of incidence (10,25).

Definition and Clinical Features

The descriptive ILAE-definition of JME summarizes the typical clinical features: “Impulsive petit mal [= myoclonic jerks, the author] appears around puberty and is characterized by seizures with bilateral, single or repetitive, arrhythmic, irregular myoclonic jerks, predominantly in the arms. Jerks may cause some patients to fall suddenly. No disturbance of consciousness is noticeable. (…) Often, there are GTCS and, less often, infrequent absences. The seizures usually occur shortly after awakening and are often precipitated by sleep deprivation. Interictal and ictal EEG have rapid, generalized, often irregular spike-waves and polyspike-waves. (…) Response to appropriate drugs is good” (2).

Age at onset is between 8 and 26 years of age (9); however, more than three in four patients have seizure onset between the ages of 12 and 18 years, with a mean onset age of 14 years (26).

Though the predominant and name-giving seizure type in JME are myoclonic jerks, commonly the first GTCS is the event that results in referral to a specialized physician and in making the correct diagnosis. In almost all patients, the first GTCS is preceded by myoclonic seizures for a couple of months, which at first may not be judged by all patients and their parents to be pathologic. In the first thorough and systematic characterization of JME by the German neurologists Janz and Christian in 1957, sleep deprivation and consumption of unusually large amounts of alcohol were reported to trigger both myoclonic jerks and GTCS (28). Further seizure-facilitating factors include stress, fatigue, and menses. A common phenomenon in JME (almost 50% of patients) is praxis-induction; that is, myoclonic seizures or generalized EEG discharges without jerks are triggered by manual activity or even by higher cognitive tasks such as calculation, reading, or decisionmaking (29).

Myoclonic jerks and GTCS tend to occur within 30 to 60 min after awakening, and this also accounts for an afternoon nap. Myoclonic seizures are brief, involuntary, symmetric, but sometimes irregular; jerks most commonly involve shoulders and arms. The legs may also be affected, and seizure-associated falls are possible. During myoclonic seizures, consciousness is unimpaired. Myoclonic jerks may occur in series, and they may build up to and eventually cease with generalized tonic–clonic seizures. This sometimes results in misdiagnosis of a partial seizure (myoclonic seizures can be asymmetric) evolving to a secondary GTCS. However, both myoclonic seizures and GTCS in JME are primarily generalized seizures.

Beyond seizures, JME may be associated with some specific personality traits. In their landmark report on JME in 1957, Janz and Christian characterized patients as impulsive, immature, and unrealiable, resulting in difficulties in their social life and in management of their epilepsy (28). Systematic analysis and quantification of personality traits in 42 JME patients as compared to age- and sex-matched controls demonstrated significantly higher scores on “Novelty Seeking” and “Harm Avoidance,” the latter indicating less tolerance of frustration and higher discomfort in uncertain situations (30). In patients with JME and—to a lesser degree—in their otherwise healthy siblings, impairment of prospective memory has been reported, which is highly dependent of executive functions (31). This sibling study suggests that frontal lobe dysfunctions in JME represent an additional clinical feature of the underlying neurobiologic alterations.

EEG

The interictal EEG shows normal background activity and generalized spike– or polyspike–wave discharges at approximately 3/seconds with frontal preponderance, that is, maximal expression in frontal leads. Discharges are best detected shortly after awakening. Photoparoxysmal responses with or without myoclonic jerks have been observed in 30% of patients (32). In the ictal EEG, polyspike–wave discharges that consist of up to 20 spikes directly precede the myoclonic jerks (33) (Figure 21.4). Polyspike–wave discharges are typical for JME, but these EEG findings are not pathognomonic as they may also be found in epilepsy with grand mal on awakening.

Treatment

The UK trial comparing standard and new antiepileptic drugs (SANAD) in patients with GGE, including JME, has demonstrated significant superiority of valproic acid compared to both lamotrigine and topiramate in regard of time-to-treatment failure (34). This study confirms previous findings on the excellent efficacy of valproic acid in JME, resulting in complete seizure control in 85% of patients (35,36). Due to the teratogenic risk of valproic acid, alternatives are urgently needed for female patients. Lamotrigine has been compared to valproic acid in a randomized open-label approach, and both drugs were highly efficacious with more than 80% seizure-free patients after 4 months (37). Lamotrigine tended to be better tolerated compared to valproic acid. On the other hand, there have been a couple of reports on proconvulsant effects of the sodium channel blocker lamotrigine, which in particular has the potential to aggravate myoclonic jerks (38,39). Paradoxical proconvulsant effects with facilitation of myoclonic seizures are also well-known with carbamazepine (40), oxcarbazepine (22), and phenytoin (28). In cases of JME that are difficult to treat, add-on levetiracetam reduced median seizure frequency by 67% compared to 14% reduction with placebo (17). In nonrandomized small case series, levetiracetam monotherapy resulted in seizure freedom in 50% to 80% of JME patients (41,42). Levetiracetam seems to be particularly efficacious in controlling myoclonic jerks (43).

In summary, JME is best treated with valproic acid; if teratogenicity is a concern or if valproic acid failed, levetiracetam seems to be a promising alternative.

FIGURE 21.4 A 15-year–old boy with juvenile myoclonic epilepsy since his 14th year of life. Epilepsy started with myoclonic jerks occurring within 20 min after awakening in the morning. Within 1 month, the patient experienced his first generalized tonic seizure early in the morning after a night with 5 hours sleep only. At the time of the EEG, the patient was treated with 2,000 mg levetiracetam. The left and right EEG trace show the same event with different temporal resolutions (right double that of left). The event is characterized by two generalized spike–wave discharges at 3 to 4/sec followed by high-frequency polyspikes for 0.5 sec. The myoclonic jerk follows the end of the polyspikes and is reflected by the movement artifacts in the EKG trace (at the bottom).

Prognosis

Some 30 years ago, the axiomatic dogma was that JME requires lifelong anti-ictal treatment; otherwise, seizure recurrence would be almost inevitable.

In the last couple of years, five retrospective studies on long-term outcome of JME have been published (7,25,44–46). A total of 208 patients were followed up for at least 20 years. In our own study, the mean follow-up period was 45 years (46). Terminal 5-year seizure remission was seen in between 27% and 68% of all patients, and for at least 5 years, 8% to 26% of all patients, in addition to seizure freedom, were off anti-ictal medication (Table 21.1). However, it is unclear how many patients in the course of their disease had seizure relapse after withdrawal of anti-ictal medication and then restarted regular drug intake.

We identified manifestations of additional absence seizures at onset of JME as an independent predictor for lack of terminal 5-year seizure remission (46). In univariate analysis, other studies demonstrated that a long duration of epilepsy with unsuccessful treatment, anti-ictal polytherapy (45), and GTCS preceded by bilateral myoclonic seizures (7,45) are significantly associated with lack of seizure freedom. There was a general trend that the older the patients were, the more likely they were in remission.

In the majority of studies, long-term psychosocial outcome was rather unfavorable. A study from Canada reported that 17 out of 23 patients (74%) had at least one major unfavorable social outcome, which was defined as failure to complete high school, unplanned pregnancy, depression, unemployment, living alone, and never in a romantic relationship longer than 3 months (25). In contrast to the physicians’ rating, 65% to 77% of the patients reported that they were “very satisfied” with their health, work, friendships, and social life. In that study, there was no clear relationship between social outcome and seizure outcome. While this missing relation was confirmed in another study that reported favorable social outcome in only one-third of patients (7), a German study demonstrated a significant correlation between lack of seizure freedom and poor psychosocial outcome (47).

We compared psychosocial outcome in 41 patients with JME and 41 age-, sex- and severity of epilepsy-matched patients with absence epilepsy (AE) (48). This approach was chosen to control for the impact of seizures, anti-ictal substances, and social stigma on psychosocial long-term outcome. Interestingly, outcome in JME patients was favorable; 80.5% of patients had never been unemployed for more than 1 year, 90.2% were well integrated into social context, and quality of life in all inquired subdomains revealed high scores. Compared with AE controls, JME patients did not perform worse regarding psychosocial outcome; rate of university access and degrees in JME patients was even higher (70% vs. 34%, P = .001). Similar psychosocial outcomes in JME and AE patients argue against specific neurobiologic alterations in JME that may predispose the patient to social deficits.

In summary, long-term seizure outcome in JME is excellent, and withdrawal of anti-ictal drugs in the later course of the disease may be justified. The psychosocial outcome is reported to be suboptimal in a relevant proportion of JME patients, but favorable prognosis is possible if patients grow up and develop in a stimulating environment.

TABLE 21.1

EPILEPSY WITH GRAND MAL ONLY (ON AWAKENING OR BY RANDOM)

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