Idiopathic Generalized Epilepsies: A Review and Modern Approach

Abstract

Idiopathic generalized epilepsies (IGEs) (1) constitute nearly one third of all epilepsies. They are genetically determined and affect otherwise normal people of both sexes and all races. IGEs manifest with typical absences, myoclonic jerks, and generalized tonic–clonic seizures, alone or in varying combinations and severity. Seizure-precipitating factors and photosensitivity are common. Most seizures occur on awakening, particularly after sleep deprivation. Absence status epilepticus is frequent. Syndromes of IGE usually start in childhood or adolescence, but some have an adult onset. They are usually lifelong, although a few are age-related. The diagnosis of IGE is usually easy though IGEs are frequently misdiagnosed as nonepileptic or other focal and symptomatic epileptic disorders. The electroencephalogram (EEG) is the most sensitive test in the diagnosis and confirmation of IGE. EEG shows generalized discharges of spikes, polyspikes, or spike/polyspike-wave either ictally or interictally. These discharges often are precipitated by hyperventilation, sleep deprivation, and intermittent photic stimulation. Inconspicuous clinical manifestations become apparent on video EEG and with breath counting during hyperventilation. The EEG is unlikely to be normal in untreated patients. In suspected cases with normal, routine awake EEG, an EEG during sleep and awakening should be obtained. Molecular genetic analyses have led to important breakthroughs in the identification of candidate genes and loci; genetic heterogeneity is common. Treatment of IGE is demanding for two main reasons. First, some antiepileptic drugs (AEDs) of benefit in focal epilepsies may be deleterious in IGE. Secondly, efficacy of AEDs differs even within seizures of IGE. This is because the generation of absences, for example, is due to a predominance of inhibitory activity, in contrast with generalized convulsive seizures in which an excess of excitatory activity is present. Most seizures and syndromes of IGE respond well to appropriate AEDs, but treatment is often lifelong. Advice regarding circadian distribution, lifestyle, and seizure precipitants may be as important as drug treatment. Avoidance of precipitating factors and adherence to long-term medication is essential to avoid seizures. Children and women with IGE merit special concern and management. The fact that nearly half of patients with IGE are currently taking ill-advised AED medication is a grave problem that needs to be addressed. Misdiagnosis and inappropriate AED treatment are confounding factors accounting for avoidable major intractability, morbidity, and sometimes mortality in IGE (1). This supplement of Epilepsia is a review of modern approaches to IGEs. It comprises 22 articles prepared by leading authorities from around the world who have made significant contributions in the field of epileptology generally, as well as in their own subspecialties. The Editor's aim is to offer a thorough assessment of the current state of IGE based on the independent understanding of world experts gained through practice, research, and literature review. Therefore, this is not a consensus document. However, despite some diversity of opinions, there is apparently unanimous agreement on such important aspects of IGE as diagnosis, misdiagnosis, management errors, and appropriate and contraindicated AEDs. Peter Wolf, the newly elected President of the International League Against Epilepsy (ILAE), provides us with an in-depth knowledge of the historical aspects of IGE. “Each of the three words in this concept of idiopathic generalized epilepsy has its own complicated and sometimes problematic history,” he writes, concluding that “research progresses … have shed new light on many aspects of the idiopathic generalized epilepsies, and will probably lead to major changes in our nosological views. The time-honored term ‘generalized’ with respect to epilepsy syndromes will probably not survive these changes but become a transitional concept in the history of epilepsy.” Pierre Jallon and Patrick Latour exhaustively review the epidemiological studies of IGE, which may represent a general frequency of 15–20% of all epilepsies. However, Jallon and Latour emphasize the limitations and discrepancies of these studies because the ILAE criteria are often not respected, cryptogenic epilepsies are confused with IGEs, and EEG data are not always used for the diagnostic categorization. Mark Gardiner provides a thorough, concise review of the tremendous, fascinating advances in the genetics of IGE, which are expected to lead to new approaches to diagnosis and treatment. Many of the rare Mendelian (monogenic) IGEs are ion voltage- and receptor-mediated channelopathies. These include benign familial neonatal convulsions due to mutations in KCNQ2 or KCNQ3, generalized epilepsy with febrile seizures plus due to mutations in SCN1A, SCN2A, SCN1B, and GABRG2, autosomal-dominant juvenile myoclonic epilepsy due to a mutation in GABRA1, and mutations in CLCN2 associated with several IGE subtypes. Progress in understanding the more common familial IGEs that manifest as complex, non-Mendelian traits has inevitably been slower, but here too recent advances have occurred, implicating a range of genes, including BRD2, EFHCI, ME2, and CACNA1H. Childhood and juvenile absence epilepsy probably share a close genetic relationship, while JME appears to be a more distinct entity. Hal Blumenfeld presents a thorough critical analysis of the several cellular and molecular mechanisms that may contribute to the generation of fast spike-wave discharges that characterize IGE. He discusses evidence that electrical, neuroimaging, and molecular changes in spike-wave seizures do not involve the entire brain homogenously, but rather occur in selective thalamocortical networks, while sparing others. Improved understanding of the heterogeneous defects and selective brain regions involved will ultimately lead to more effective treatments. Antonio Delgado-Escueta and his world-expert associates provide a meticulous review of seizure phenotypes across the various IGE syndromes, their response to treatment, and an assessment of how advances in molecular genetics have influenced nosology. They stress the finding that the same seizure phenotypes respond differently to the same treatments in different IGEs, suggesting different molecular defects in IGE. Doug Nordli, Jr, masterfully describes the clinical manifestations, EEG findings, genetics, and prognosis of the syndromes of IGE officially recognized by the ILAE. He emphasizes that clinical features currently remain the cornerstone of accurate classification, and accurate classification, in turn, is the best predictor of outcome. Further genetic testing and research exploring the genotype–phenotype relationships will enhance our ability to make definitive diagnoses. Tomis Panayiotopoulos argues that there may be other syndromes of IGE that are not yet formally recognized by the ILAE. The most distinct of them is “Jeavons syndrome,” a purely reflex IGE predominantly manifesting with eyelid myoclonia and EEG abnormalities on eye closure. “Autosomal dominant cortical tremor, myoclonus and epilepsy” is a purely monogenic disorder which has been documented in numerous reports from mainly Japan and Italy. “Perioral myclonia with absences” and “IGE with phantom absences” are probable two other syndromes of IGE that are associated with a very high incidence (around 50%) of absence status epilepticus that may escape diagnosis and appropriate treatment. Less clear is the situation with early childhood IGE manifesting mainly with typical absence seizures that are distinctly different from childhood absence epilepsy and other recognized IGE syndromes. Thanos Covanis offers an excellent account of photosensitivity in IGE with regard to its pathophysiology, clinical manifestations, incidence in the various epileptic syndromes, and implications for management. He emphasizes the frequent occurrence of photically induced seizures in IGE and the need for general and specific protective measures. When AED treatment is needed, valproate monotherapy is the drug of choice, while levetiracetam appears to be a new, alternative therapeutic option. Simon Shorvon and Matthew Walker superbly review the various clinico-electrographic forms of convulsive and nonconvulsive status epilepticus, differential diagnosis, mechanisms, and treatment in IGE. The clinical semiology of the status epilepticus episodes may be similar in different epileptic conditions, but the frequency, response to treatment, and prognosis differ. Convulsive status epilepticus, for example, is surprisingly uncommon in IGE, and when it does occur, it usually responds rapidly to treatment. Typical absence status epilepticus occurs only in patients with IGE and in the syndrome of de novo absence status epilepticus of late onset. It should be differentiated from atypical absence and from complex partial status epilepticus. Although convulsive status epilepticus can result in cerebral damage, this seems unlikely in the forms of nonconvulsive status epilepticus in human IGE. Natalio Fejerman details numerous nonepileptic paroxysmal disorders that mimic and are often misdiagnosed as seizures or syndromes of IGE. He particularly examines apnea and apparent life-threatening events in infants, breath-holding spells, syncope, staring spells, psychogenic seizures, hyperventilation syndrome, narcolepsy, benign neonatal sleep myoclonus, and benign nonepileptic myoclonus, which he first described with Lombroso. Hirokazu Oguni emphasizes that differentiating between IGE and symptomatic generalized epilepsies is easy in their common forms, but sometimes in clinical practice difficulties result because of atypical or not fully developed features. He presents each syndrome of IGE and its imitators among symptomatic epilepsies with the additional benefit of well-selected illustrative cases. Colin Ferrie details how IGE imitates focal epilepsies and examines traps into which the inexperienced clinician can fall, leading to the erroneous diagnosis of a focal rather than a generalized epilepsy. Additionally, in a small number of patients with IGE, clinical or electrical features may cause problems for even the most able epileptologists. In a few subjects, both focal and generalized forms of epilepsy appear to coexist. Mike Koutroumanidis and Shelagh Smith share their expertise in scrutinizing the use and abuse of EEG in the diagnosis and management of patients with IGE. They review the morphologic and behavioral characteristics of the interictal and ictal EEG markers of IGE that should guide recording strategies to augment diagnostic yield, and they delineate those particular features that may be relevant to different IGE syndromes. They also explore the electrographic boundaries between IGE and cryptogenic/symptomatic generalized and focal epilepsies and focal/secondary generalized epilepsies, with particular relevance to the phenomena of focal abnormalities and secondary bilateral synchrony, commenting on possible diagnostic pitfalls and areas of uncertainty. John Duncan presents a fascinating examination of standard and modern applications of brain imaging in IGE. While by definition there is no neuroimaging abnormality in IGE, image processing and quantitative magnetic resonance imaging studies suggest that there may be subtle structural abnormalities. Magnetic resonance spectroscopy indicates neuronal dysfunction with differing abnormalities in the IGE subsyndromes, and high concentrations of glutamate and glutamine have been inferred in the frontal lobes, and low gamma-aminobutyric acid levels in the occipital lobe. Ictally, cerebral blood distribution at the time of absences shows an increase in the thalamus and broad decreases in the neocortex, reflecting suppression of neuronal activity, but with some increases that may indicate focal areas of activation. Positron emission tomography studies with specific ligands have the potential to clarify the functional anatomy and neurochemical circuits that underlie IGE. Carol and Peter Camfield provide step-by-step guidance for the management of children with IGE, for whom clinicians must make many important decisions, most of which are based on small case series and experience. At the time of presentation, reliability of diagnosis, initial evaluation, and choice of initial medication are the key factors for success. Investigations beyond EEG are of uncertain value but probably are not needed. Subsequently, the authors provide direction for dealing with many unanswered questions about management in the first few years of treatment, considerations for discontinuing AEDs, and preparing for adult life. Pamela Crawford reminds us emphatically that “being a woman with epilepsy is not the same as being a man with epilepsy. Epilepsy affects sexual development, menstrual cycle, aspects of contraception, fertility, and reproduction in ways that are unique to women.” Her detailed review incorporates revised statements of guidelines for women with epilepsy that are both evidence- and experience-based; it examines every aspect of a girl's or woman's life that can be affected by epilepsy and AEDs. Selim Benbadis deals with practical management issues for IGE, from the clinical diagnosis of seizures and syndromes to appropriate and inappropriate antiepileptic medications. He stresses that some AEDs, such as carbamazepine, phenytoin, gabapentin, and tiagabine, are ill-advised for treating patients with IGE because they are either ineffective or exacerbate absences and myoclonic seizures. Their use is the main cause of “pseudo-intractability” in IGE. Valproate is the most effective AED. The role of newer AEDs in IGE is continuously evolving, but only four—lamotrigine, levetiracetam, topiramate, and zonisamide—appear effective in IGE. Antiepileptic drugs are the cornerstone of therapy for IGE. Valproate is the most effective of the older AEDs, but there are significant concerns about adverse effects, particularly in women. Ethosuximide is only for absence seizures and negative myoclonus, clonazepam is primarily for myoclonic jerks, and the role of clobazam in IGE is still unclear. Carbamazepine and phenytoin often aggravate IGE. Over the past 15 years, 10 new AEDs have been licensed for the treatment of focal epilepsies in a continuing quest for medications that are more effective and less damaging than the older pharmacological agents. Despite this progress, only four of these AEDs, namely lamotrigine, levetiracetam, topiramate, and zonisamide, have a sufficiently broad spectrum of activity to be useful in IGE. The others are contraindicated or ineffective. João Chaves and Ley Sander provide a thorough review of a strange situation whereby certain AEDs exacerbate rather than ameliorate IGE. Aggravation may be due to a paradoxical reaction, paradoxical intoxication, drug-induced encephalopathy, sedative effects, or inappropriate use of a particular AED. It is important to distinguish the different circumstances, because they determine appropriate management. Carbamazepine, oxcarbazepine, phenytoin, vigabatrin, tiagabine, gabapentin, and pregabalin commonly exacerbate absence seizures, myoclonic jerks, or both and should not be used in the treatment of IGE. Valproate, lamotrigine, levetiracetam, topiramate, and zonisamide are appropriate medications and, therefore, less likely to cause seizure exacerbations. Philip Patsalos scrutinizes the mechanisms of action and the pharmacokinetic and pharmacodynamic properties of the AEDs that are appropriate in the treatment of IGE. These are the older AEDs valproate, ethosuximide, clobazam, and clonazepam, and the newer AEDs lamotrigine, levetiracetam, topiramate, and zonisamide. These AEDs do not appear to have a common mechanism of action; both inhibitory GABAergic and excitatory glutamergic mechanisms are involved, or the mechanisms are multiple. Levetiracetam is unique in that it may act via a specific binding site in the brain. All these AEDs, with the exception of lamotrigine and levetiracetam, undergo elimination as a result of extensive metabolism by hepatic cytochrome P450 enzymes, which are highly amenable to induction and inhibition by other drugs and, therefore, susceptible to pharmacokinetic interactions. Lamotrigine metabolism is via hepatic glucuronidation, a process that is also susceptible to induction and inhibition by concurrent drugs. Levetiracetam is minimally metabolized (by hydrolysis), excreted predominantly unchanged in urine, and to date has not been associated with any clinically significant pharmacokinetic interactions. Further, Patsalos directly compares these AEDs by use of his own semiquantitative pharmacokinetic rating system, based on 16 pharmacokinetic characteristics. Valproic acid is rated lowest mostly because of its nonlinear pharmacokinetics, extensive hepatic metabolism, and high propensity to interact with other AEDs and non-AEDs. Levetiracetam rates highest, while topiramate is in second place. Nikolas Hitiris and Martin Brodie scrutinize reports of evidence-based treatment of seizures and syndromes of IGE with older AEDs; the reports were located through an extensive search of Medline and Embase. Good-quality evidence is sparse, and only a few trials have examined the effects of the older AEDs in the epilepsy syndromes. Childhood absence epilepsy is the only IGE syndrome for which there is reasonable evidence of efficacy from randomized, comparative trials, with ethosuximide and valproate demonstrating equivalence in its treatment. Valproate can be regarded as the recommended first-line treatment for juvenile myoclonic epilepsy based on case series reports. Studies in patients with generalized tonic–clonic seizures have not separated idiopathic from secondary generalized events. Therapy for the other IGE syndromes lacks evidence other than a few case reports and diverse expert opinions. Treatment with other drugs, such as carbamazepine and phenytoin, can lead to poor outcomes, with the result that some patients are being categorized as having refractory epilepsy. Greg Bergey provides a meticulous review of the available data from well-controlled trials from which evidence-based treatment recommendations of the IGEs with second-generation AEDs can be derived. He also discusses some less rigorous reports of selected class III and IV studies to frame the potential spectrum of action of a given AED, and to provide suggestions for future well-designed studies. The initial pivotal controlled trials of most new AEDs are as adjunctive therapy for patients with refractory partial seizures, because these patients are the most readily available for these well-established trial designs. After approval, these new AEDs may be tried in IGE, and indeed there is a growing body of literature that lamotrigine, levetiracetam, topiramate, and zonisamide may have efficacy for a broad spectrum of seizure types including those of IGE. Large, randomized, well-controlled trials designed to provide Class I or II evidence, however, face a number of recruitment hurdles in IGE. To date good Class I and II studies exist to support the use of lamotrigine in absence seizures, topiramate in primarily generalized tonic clonic seizures, and levetiracetam in IGEs with myoclonic jerks. Richard Grünewald briefly reviews the mechanisms of action and pharmacological properties of levetiracetam and comprehensively examines the evidence in regard to its efficacy and safety in IGE. Levetiracetam has many of the properties of an ideal AED, including rapid absorption, linear pharmacokinetics, and few drug interactions. Its mechanism of action is novel, entirely different from those of every other AED. Tolerability is generally excellent in both adults and children. Levetiracetam is probably the best new AED in the treatment of juvenile myoclonic epilepsy, with high and sustained efficacy. More than 60% of patients with intractable juvenile myoclonic epilepsy became seizure-free with levetiracetam monotherapy or polytherapy. A recent double-blind, multicenter, randomized placebo-controlled study in 122 patients showed that levetiracetam demonstrated highly favorable efficacy and safety in the adjunctive treatment of previously uncontrolled IGE with myoclonic seizures. Levetiracetam is weight-neutral, and while information on teratogenicity is scanty, animal studies are generally reassuring; the absence of an interaction with the oral contraceptive pill makes it a reasonable alternative to valproate for women of reproductive age with IGE. It is anticipated that this volume, which has been updated to a few months before publication, would be of significant value to practicing physicians, electroencephalographers and researchers in the various aspects of IGEs. Particular emphasis has been made on the various challenges presented by patients with IGEs. The main practical message is that IGEs demand painstaking attention in regard to diagnosis, treatment and antiepileptic drug trails. This volume provides ample documentation that a diagnosis of “epilepsy” is inadequate without a precise categorization of type of seizures and type of epilepsy. IGEs require meticulous diagnostic precision to differentiate between absence seizures versus focal seizures, primarily versus secondarily GTCS and absence status epilepticus versus non-epileptic confusion or epileptic prodrome. Failure to make this differentiation results in therapeutic disasters with significant avoidable morbidity and sometimes mortality. Acknowledgment: This supplement has been supported through an unrestricted grant from UCB S.A., manufacturers of levetiracetam (Keppra®).