Idiopathic Generalized Epilepsy with Generalized and Other Seizures in Adolescence (2001)

We owe a great debt to Dieter Janz (1,2) and also to Peter Wolf (3–5) for their effort in describing, dissecting, and defining the idiopathic generalized epilepsies (IGEs), particularly those with onset during adolescence and adult life. Myoclonic epilepsy was of course clearly recognized by British and North American neurologists since Gowers (6), William Lennox (7,8), and Francis McNaughton, and the characteristic multiple spike-and-wave EEG discharge of myoclonic epilepsy was identified early by the Jasper school of clinical neurophysiology. The pioneering work of Dieter Janz was, mainly for linguistic reasons and because of its unusual terminology, ignored by Anglophone neurology. The contribution of Escueta and Bacsal (9) in drawing attention to juvenile myoclonic epilepsy (JME) was crucial in bringing the studies of Janz's school to the attention of the North American neurological community. Janz, with his disciples and colleagues, identified several IGE syndromes that had characteristic onset within the adolescent age range: JME, juvenile absence epilepsy, and epilepsy with grand mal seizures on awakening. He was, of course, aware of the overlap between these forms, and this is clearly represented in his well-known schematic diagrams. He based his classification on criteria that took into account historic, clinical, and electrographic aspects (10). In a critique published in the volume “Epileptic Syndromes and Seizures,” edited by Wolf, Janz (10) deplored the absence of a diagnosis of epilepsy on awakening in the several hundred patients with epilepsy studied by Manford et al. (11). He asked whether such patients would be evaluated and classified differently in the United States and England, and the answer is manifestly: yes. The classification of the epilepsies and of epileptic syndromes is an ongoing exercise driven by the need for uniform and universally acceptable criteria and definitions (12). The classification aims at improving our understanding of pathophysiologic mechanisms, refining the results of treatment, and, in this era of great strides in molecular biology, clarifying the genetics of the epilepsies. It behooves us to reexamine the definitions and criteria for recognition of epileptic syndromes and, because of the question raised by Janz, it seems appropriate to begin by another look at epilepsy on awakening. The majority of generalized tonic-clonic (TC) seizures in all forms of IGE occur after awakening and are particularly likely to happen when the person is aroused after sleep deprivation followed by brief sleep (13–17). This relationship to epilepsy on awakening is particularly clear in patients with JME in whom sleep deprivation is known to be the major activating factor, with alcohol being second, and stress or fatigue third. Considering pyknoleptic and nonpyknoleptic absences, Janz et al. found that when TC seizures were associated, >90% of these also occurred on awakening. Thus a close relationship to the sleep–waking cycle is present in all these three groups of patients with IGE, and furthermore, myoclonus and absence status share this tendency to occur after awakening, thus in the morning after sleep, presumably because of similar underlying mechanisms. A second peak of TC seizures in epilepsy on awakening occurs during the evening, after work, during relaxation, or perhaps in relation to fatigue (18). An increased frequency of absences during relaxation has long been known, coupled with the lesser likelihood of absences occurring during activities requiring attention. One may speculate about the effect of arousal on the reduction of attacks in such situations. Thus activation by relaxation is also not specific for the TC seizures of epilepsy on awakening. Janz concluded that six attacks were required before making such a diagnosis (1,10). Although a tendency to recurrence of seizures is crucial for a diagnosis of epilepsy, current practice dictates more investigation at the onset, with the aim of obtaining an electroclinical correlation. This is of paramount importance in establishing a prognosis and in making a decision to treat. The dictum of not treating the first seizure is generally accepted, but the role of the patient and family in making such a decision is an important one, and there is scope for flexibility in this regard. The role of triggering factors in IGE is of great importance. As Janz has already stressed, avoidance of such triggering factors may be possible in some individuals who would thus not reach the crucial number of six attacks so far required for this diagnosis. The concept of “oligoepilepsies” proposed by Janz, in which occasional seizures separated by long intervals are observed, has not been universally accepted, although there is no doubt that the intrinsic severity of the process is important, in addition to the presence of triggers, in the recurrence of attacks. Many occasional seizures or so-called “Gelegenheitsanfälle” may be manifestations of IGE, although probably not all, because some may be due to idiopathic partial epilepsies or symptomatic forms. Clearly the diagnosis of “oligoepilepsy” varies with the depth of investigation and, because follow-up is crucial, it is a function of longitudinal observation as well. Finally, the requirement of six seizures for a diagnosis of epilepsy on awakening may not be appropriate in this era that has seen considerable improvement in the treatment of IGE with valproate (VPA) and we hope with other agents such as lamotrigine (LTG) and levetiracetam, particularly if minor attacks coexist. Thus, a history of six major attacks would at present imply either fairly severe disease or poor compliance with medication, sleep requirements, or both. In his careful early study of 1969 (18), Janz concluded that two thirds of patients with grand mal on awakening had other seizures as well, and in three fourths, these were clinically recognizable patterns of IGE. Mostly the associated attack patterns were myoclonus and/or absence. There was considerable variation in how such patients were diagnosed in various centers from this point of view in Germany, France, and the U.K. (10). This was most likely due to differences in perspective and to ascertainment bias rather than to variation in the actual clinical symptoms. It is generally agreed that myoclonus for instance, but also absence or absence status, may be ignored by the patient or remain undiagnosed by the physician until a generalized seizure occurs. Retrospective inquiry is often useful in suggesting the diagnosis and certainly in orienting the investigation, but cannot lay claim to statistically valid accuracy (26). Should one attempt to diagnose the different IGE syndromes on the basis of predominance of seizure pattern, age at onset, or clinical disability? Certainly recognition of the presence of absence and myoclonus has important repercussions on the choice of antiepileptic agents (AEDs) and on prognosis. A major reason for inadequate seizure control potentially leading to cognitive decline and downward social mobility is the use of drugs such as phenytoin (PHT), carbamazepine (CBZ), or barbiturates, although even these may at times be effective. Recognizing the importance of the need for control of minor seizures as a prerequisite for the control of major attacks may lead to complete seizure control in many patients with JME or JAE. Their attacks may have been uncontrolled for years, because of either inappropriate medication or inappropriate lifestyle, and frequently also because of lack of avoidance of proven triggering factors. It is not the purpose of this article to revive the question of syndromic approaches versus a biologic continuum. The value of identifying epileptic syndromes has now been acknowledged by epileptologists worldwide. Yet in individual patients, the need to situate them within the biologic continuum for therapeutic and prognostic reasons is equally important (19). Until the molecular genetic basis of the IGEs is clarified, it seems important to retain the syndromes of juvenile IGE with myoclonus and/or absence, the latter overlapping also with childhood absence epilepsy. There are cogent reasons also for considering IGE with exclusively generalized seizures separately, not least because of some therapeutic implications. The onset of these disorders is during adolescence, a period of important psychological and personality development. Peer pressure and a need to conform are important features. Recognition of endogenous factors leading to seizure recurrence is important but is not necessarily spontaneously realized by patients and their families. The avoidance of seizure triggers, particularly lack of sleep and alcohol, should be stressed to patients and friends. And yet, despite this, lack of compliance is common in those with recurrent attacks (20). A learning process is thus required for seizure control, and the patients as well as the family should be seen, if possible after every recurrence, to clarify the presence of a potential trigger and to further such a learning process. Janz has, in addition (14), suggested the presence of a psychological disorder manifested by “suggestibility, a tendency to be easily misled, a weakness of character, inability to withstand temptation, a tendency to conceal the circumstances of the seizure, and a conflict between knowledge and desire.” Whether there is in fact an underlying generic personality disorder related to the mechanisms of IGE is unclear, but there is not sufficient evidence to assume this. The type of behavior Janz describes is certainly not ubiquitous in adolescents with epilepsy. It may well not be due to intrinsic components of the disease process related to anatomic factors such as the frontal predominance of discharges or to abnormal thalamocortical mechanisms. There is a certain analogy with other adolescent behavioral problems, and this area of epileptology has not been adequately explored. Wolf (3–5) reviewed the prevalence studies of GMA (GM on awakening), GMS (GM during sleep), and random or diffuse GM. In a series of studies, GMA occurred in between 16.8 and 40%, GMS in 28–33%, and GM at random in 18–26%. In one study, 36% had daytime GM attacks. How many of these patients also had minor seizures is not clear. It is important to determine whether such patients have minor attacks, or petit mal status. From a practical clinical standpoint, identification of minor attacks is achieved by repeated careful history taking from patients and eyewitnesses, although video-monitoring may yield even more cases with absence or myoclonus. It is, however, obvious that there are patients who have, as far as one can tell, only generalized TC seizures, and that these may occur on awakening but also during the day, during sleep, or at random. Seizures on awakening have been preferentially studied, perhaps because of Janz' eminence, to the detriment of patients with attacks during sleep or at random about whom very little is written and who have not received syndromic acceptance in the “Guide Bleu”(21) or in the Classification of Epilepsies and Epileptic Syndromes (12). Recognition of these subgroups seems important, but focusing on the relation to the sleep–waking cycle as the major diagnostic criterion introduces a certain, and probably unjustified, bias. Thus it would seem reasonable in the projected revision of the International Classification to expand the category of major seizures (GM) to include as well patients with IGE who have attacks only during sleep or at random. An interesting analysis by epileptologists who were well aware of the various patterns was carried out in 101 patients (22). The included patients had at least two generalized seizures, generalized spike-and-wave, and onset between ages 8 and 20 years. On the basis of a searching clinical history, 20% had myoclonus, absences occurred in 37%, and both myoclonus and absence in 26%; 17% had generalized seizures alone. Age at onset was somewhat lower in patients with absence, suggesting some relationship to childhood absence epilepsy. Patients who had absence and myoclonus tended to behave like those with myoclonus alone, with more frequent premonitory jerks and greater sensitivity to sleep deprivation. In addition there are individuals not included in this study, who have myoclonic jerks alone, probably also due to JME. The mother of a patient with classic JME had had such myoclonic jerks as a student at Oxford but never a generalized attack. How often this occurs and whether this also happens with absences alone during adolescence is unclear. Two major groups emerge: Generalized TC seizures with myoclonus, absence or absence status, or both. Generalized TC seizures alone. This division has important implications as far as treatment is concerned because minor seizures respond better to drugs like VPPA, which may lead to complete control. As far as driving is concerned, in most countries, myoclonus is not a contraindication, whereas absence is, despite the fact that awareness may be only incompletely lost (23–25). These major categories may be subdivided further: Generalized TC seizures with myoclonus, absence or absence status, or both: Juvenile myoclonic epilepsy b. Juvenile myoclonic and absence epilepsy c. Juvenile absence epilepsy Generalized TC seizures alone Seizures on awakening b. Seizures during sleep c. Seizures at random Such further subdivisions correspond to reality and would seem to take into account the various seizure types; conversely, it also is clear that there is some variation in ages at onset, which should be recognized, and thus one should refer to IGEs with onset mainly during adolescence (see also 24 for review). The practical application of a classification of the IGEs may not require division into all the subgroups outlined. However, recognition of all seizure patterns present in any given patient or family is obviously a requirement for optimal clinical investigation and treatment. It could be argued that a separate category should be made for patients with only myoclonus or absence. However, although such patients have not had TC seizures, with the important medical and psychosocial implications of such attacks, there is no evidence that these patients have syndromes that have fundamental biologic differences from cases with major seizures as well. Here the emphasis has been on IGE syndromes in adolescence. It is clear that similar clinical patterns can begin in young adult life and sometimes in middle and perhaps the later adult years. Additionally there are particular IGE syndromes in adult life, of which late-onset absence status is the best defined. More systematic study of adult-onset IGE is needed to clarify the syndromes involved. There also are classification issues in IGE in the first decade. Childhood absence epilepsy is quite well defined, but there are many children with TC seizures alone in whom syndromic diagnosis is difficult. Some have a personal or family history of febrile seizures, and belong within the spectrum of generalized epilepsy with febrile seizures plus (27), but other children cannot otherwise be classified. Again, this important group requires more detailed study before a practical classification can be proposed. Eventually the contribution of different genes may clarify the reasons for overlap between the polygenic forms of IGE and probably their age dependency as well. It will then be time for another, perhaps more rational classification.