Summary: The prevalence of idiopathic generalized epilepsies (IGEs) has been assessed as being 15–20% of all epilepsies. The seizure types in IGEs are typical absences, myoclonic jerks, and generalized tonic–clonic seizures (TCS), alone or in varying combinations and with variable severity. The seizures tend to be more frequent on awakening and with sleep deprivation. This group of clinical conditions includes among others, age-related epilepsy syndromes of adolescence such as juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with generalized TCS or epilepsy with grand mal on awakening (EGMA). The classification of IGEs follows two schools of thought; one maintains that IGEs are a group of different and separate syndromes while the other suggests that IGEs are one biological continuum. Patients with IGEs may have mild impairment of cognitive functions, especially verbal memory and other frontal lobe functions, despite a normal IQ, and some seem to have characteristic personality traits, although further studies are needed to support this theory. They appear to lack a degree of self-control, to neglect their physical needs, and are poorly compliant with therapy. Some patients become obstinate and are impressionable. The cognitive and behavioral aspects of these patients suggest an involvement of frontal lobes.
Idiopathic generalized epilepsies (IGEs) constitute a large and heterogeneous group. The seizure types in IGEs are typical absences, myoclonic jerks, and generalized tonic–clonic seizures (TCS), alone or in varying combinations and with variable severity. The seizures tend to occur on awakening and with sleep deprivation; photosensitivity, and other seizure precipitants are common. Seizure onset is often in childhood or in adolescence, although some have an adult onset. IGEs have a genetic origin and have the same prevalence in males and females of all races (1). Although epidemiological data are still scarce, the prevalence of IGEs can has been assessed as 15–20% of all epilepsies (2).
IGEs are only in part recognized by the ILAE Classification (3). The IGEs recognized by the ILAE are benign myoclonic epilepsy in infancy, generalized epilepsy with febrile seizures plus, epilepsy with myoclonic astatic seizures (Doose syndrome), childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized TCS only (4). There is, also, a group of IGEs, which are not included in ILAE Classification. They include, among others: IGEs with absences of early childhood, perioral myoclonia with absences, IGEs with phantom absences, eyelid myoclonia with absences (Jeavons syndrome), and autosomal-dominant cortical tremor myoclonus and epilepsy (5). Data about these syndromes are scarce.
At present the two schools of thought, with opposite views, are that IGEs are a group of different and separate syndromes or that IGEs are different facets of a broader neurobiological spectrum of generalized epilepsy. The first theory is based on the search for precise clinical, electrophysiological, and genetic findings, which are needed for an exact syndromic diagnosis. This point of view emphasizes the importance of the criteria to be used for the differential diagnosis, which is the main reason for the recent attempt to revise the classification of the epilepsies (6). In contrast, the second theory requires an easier diagnostic approach, and implies that the differential diagnosis between these syndromes does not give essential information for prognosis and treatment. The current evidence is not in favor of one or the other theory.
Generalized idiopathic age-related epilepsy syndromes in adolescents include JAE or Friedman syndrome JME or Janz syndrome, and IGE with generalized TCS or epilepsy with grand mal on awakening (EGMA) (3). These syndromes differ principally in their predominant seizure types but they may also differ in electroclinical semiology (7). The age of onset may be different among the syndromes. Patients with childhood onset epilepsy probably have a better prognosis, but this assumption is not supported by the available data.
Juvenile absence epilepsy
JAE usually appears between age 10 and 16 years (average 13), although there is a childhood form with an age of onset at 6–8 years (8). This clinical condition has a strong genetic component (linkage to chromosomes 5, 8, 18, and 21). The absences of JAE are not phenomenologically different from the absences of CAE, but are clinically less frequent (sporadic), and with less severe impairment of consciousness (9). They tend to be of longer duration than those in CAE. CAE seems to have a better prognosis, but this last assumption is not entirely supported by the available data (8).
There are no significant differences in sex distribution. Clinically isolated absences are rare; most patients (46%) also have generalized TCS and sporadic myoclonic jerks (8). In most cases absence seizures precede the onset of TCS; in about a quarter of cases, TCS precede the occurrence of absences (10). TCS are often precipitated by sleep deprivation or awakening. Interictal EEG abnormalities are mostly slow waves >3 Hz. The prognosis of this syndrome is good; although seizures tend to persist for many years, patients have a good response to antiepileptic drugs.
Juvenile myoclonic epilepsy
JME is a relatively common epilepsy syndrome, comprising 5–10% of all epilepsies (11). The age of onset is similar to JAE, namely 12–18 years with an average of 15 years (8). JME is a genetic syndrome and many genetic studies have found a linkage to chromosomes 5, 2, 3, 6, and 15. The hallmarks of JME are single or arrhythmical bilateral myoclonic jerks with retained consciousness. Jerks may appear in the neck, shoulders, arms, or legs. The upper limbs are frequently affected. Only occasionally the jerks result in falls. However, patients often also have generalized TCS (9), and absence seizures are present in one-third of the cases (12).
Seizures may be precipitated by disturbances of the sleep-wake cycle, such as sleep deprivation and awakening or by alcohol abuse. The sleep-wake cycle in JME is usually characterized by falling asleep late and by difficulty in awakening, which is also late. Reflex seizures in this syndrome include photosensitivity (up to 50%), praxis (≥30%), perioral reflex myoclonias (∼ 25%), and eye-closure sensitivity (3–4%).
The interictal EEG is not specific: all types of generalized epileptiform discharges may be present. In contrast, the ictal EEG is characterized by polyspike and waves ≥3 Hz. JME often has an excellent response to adequate AED treatment but this treatment may need to be continued. Even if the patient has been free of seizures for many years, there is a high risk of relapse if the antiepileptic medication is stopped. There is insufficient data to allow identification of the factors indicating a less favorable long-term prognosis.
Epilepsy with grand mal on awakening
EGMA tends to present at a somewhat later age than JAE and JME. The age of onset ranges between 6 and 28 years, with a peak at 17 years (8). In EGMA, epilepsy with grand mal during sleep, and epilepsy with random grand mal, seizures may be also divided according to their correlation with the phases of the sleep-wake cycle. Beyond the description of a trait, this is an attempt to reach a better understanding of the pathophysiology of epilepsies by investigating their biological features.
By definition, in EGMA generalized TCS occur predominantly within 1–2 h after awakening; the second seizure peak is during the evening, when the patient may be relaxing. This syndrome is regarded as a broad category of low specificity that may encompass more specific syndromes (13). Most patients (81%) have, in addition, absences or myoclonic jerks (or both) (10). Because of inadequacies in history taking, this syndrome is generally underdiagnosed. A genetic predisposition is frequent.
There are nonspecific bilateral epileptiform patterns in the EEG. In this syndrome, a response to adequate antiepileptic medication is good.
COGNITIVE AND BEHAVIORAL OUTCOME
The cognitive outcome of people with IGEs has been investigated quite extensively. The performance of this group has been variable, with some patients showing marked impairment and others none (14). A high frequency of mild impairment has been found in some tasks exploring frontal functions and in primary memory functions, with a normal IQ (concept formation, abstract reasoning, verbal fluency and mental flexibility, cognitive speed, planning, and organization) (15). Using tests of cognitive performance in JME patients and controls (Mini Mental State Examination, verbal and visual memory, visuospatial, frontal function attention) significant differences were found in verbal and visual memory, frontal and visuospatial function (16). The presence of seizures had a negative effect on cognitive scores.
With reference to the cognitive outcome of IGEs, specifically in patients with absence or TCS with well-controlled seizures, in a case-control study, Henkin et al. found significant attention deficits in both groups of patients. Patients with absence seizures scored significantly lower in verbal learning, memory, word fluency, and controlled fine motor responses, excluding nonverbal memory, compared to people with TCS and healthy controls (17). These results suggest a long-term risk of learning impairment for children with IGE, even if they have normal intelligence and the seizures are well controlled. Swartz et al. examined memory functions with specific frontal psychological tests in patients with JME, compared with patients who had frontal lobe epilepsy (FLE) and healthy controls. JME patients scored better than FLE patients but worse than controls (18). In these subjects, neuroimaging studies with positron emission tomography found decreased glucose uptake in the dorsolateral prefrontal cortex and a decreased activation in the dorsolateral prefrontal area compared to controls (19).
Taken together, these data suggest subtle frontal impairment of psychological functions in people with IGEs.
Until now, little attention has been paid to the behavioral aspects of IGEs, despite the fact that behavior may have a profound affect on social relationships, education, and the options for vocational training or employment. Further, there has been little investigation of the personality and behavioral characteristics of people with these syndromes using standardized scales and there have not been systematic studies in large samples.
There is general agreement that the personality changes actually observed in patients with epilepsy mostly refer to the population with chronic temporal lobe epilepsy (20). Geschwind described in many of these patients characteristic personality traits (hyposexuality, religious ideas, hypergraphia, and viscosity) (21). These traits are often followed by suggestibility and immaturity (as if stuck in continuous adolescence) (22). In contrast with the TLE personality, many patients with IGE, especially those with JME, seem to have attractive but unstable, suggestible, unreliable, and rather immature personalities which often result in inadequate social adjustment (23). The immature personality traits may include indifference to the disorder, lack of discipline, unstable self-confidence, denial of problems and conflicts and alcohol abuse.
According to the available information, the differences in personality traits between the IGEs seem to be mild, especially if compared to the substantial differences between IGE personality and TLE personality (24).
EGMA patients, investigated with two personality tests (Rorschach and Szondi), were described as extrovert, undisciplined, and with difficulties in recognizing their own limits in relation to the external world (25).
Characteristics such as impressionability, openness, and awareness to the point of being easily distracted, make these patients appear alert and clever, but cause them problems when tasks requiring resoluteness, patience, and perseverance are concerned.
Interviews by questionnaire, carried out in Germany comparing IGE (specifically JME) and TLE patients, found that JME patients feel worse than TLE patients in the morning and better in late afternoon (26).
Some old studies (27,28) compared JME with idiopathic tonic–clonic epilepsy and found no differences between the two groups with regard to social conditions, education, and intelligence but social interactions, experiences and discrimination were more impaired in patients with JME. In a case-control study comparing patients with JME to those with TLE, diabetes and healthy controls, Perini, using the Schedule for affective disorders and schizophrenia found 80% of patients with TLE had psychiatric disorders compared to 22% of patients with JME and 10% of patients with diabetes. More specifically, depression was less frequent in people with JME (16% vs. 55% in TLE and 20% in diabetes) (29). Gelisse et al., in a retrospective study on psychiatric comorbidity in 170 patients with JME, found personality disorders in 24 cases (14%): borderline in 11 cases, dependent in five cases, histrionic in two cases, obsessive-compulsive in one case, and not otherwise specified in five cases (30). Personality disorders may represent a further challenge in the comprehensive care of these patients.
According to Janz, some of these personality traits, such as limited self-control, suggestibility, distractibility, and indifference to physical needs, associated with cognitive dysfunction and neuroradiological alterations, suggest an involvement of frontal lobes (27). This theory is supported by increased bilateral frontal or frontocentral spike-wave activity in this type of epilepsy (31,32). Also, bilateral cortical microdysgenesis was found to be more pronounced in the frontal regions in these patients (33–35). Frontal lobe function is crucial for the ability to suppress behavioral impulses (36).
The classification of IGEs in adolescence is as yet unclear. Despite some differences in clinical manifestation and EEG abnormalities, patients with all these syndromes achieve good seizure control in a high proportion of cases. Moreover, they usually respond to the same antiepileptic drugs.
The cognitive and behavioral features of patients with IGE in adolescence can be summarized as follows:
- • Mild frontal lobe cognitive dysfunction is present in subjects with normal IQ.
- • The presence of absence seizures is a negative prognostic factor for cognitive scores.
- • Personality traits of these patients include a tendency to go to bed late, to drink alcohol, to be attractive but unstable, suggestible, unreliable, and rather immature, although further studies are needed to support this theory.