Classification and clinical features of absence epilepsies: How evidence leads to changing concepts

Abstract

To the Editors: The Commission of Classification and Terminology of the International League Against Epilepsy has an unenviable task. It has to build on the astute observations of meticulous epileptologists who have defined electroclinical entities that we now diagnose every day clinically. The concept of epilepsy syndromes is an old one, but became the focus of clinical practice and research with the 1989 Classification of Epileptic Syndromes (1989), which represented a departure from the earlier emphasis on seizure types. Originally, establishing and diagnosing syndromes was a matter of pattern recognition. By that, we mean that clinical features were perceived to cluster together, and these clusters corresponded to meaningful clinical entities. Since then, huge strides have been made in refining epilepsy syndromes with larger groups of patients as well as the recognition of new entities and subgroups within established syndromes. As with all research, syndromic concepts evolve on the basis of further observations and discoveries providing evidence that either refutes previous concepts or supports their validity. With the explosion in genomic and imaging technology, we now have promising new methods to test the biologic coherence of clinical syndromes at mechanistic and functional anatomic levels, thereby providing an objective basis for lumping or spitting clinical phenomena into biologically relevant subgroups (Berg & Blackstone, 2006). A good example of this evolutionary process is an entity we described in 1997, “Generalized Epilepsy with Febrile Seizures Plus” or GEFS+ (Scheffer & Berkovic, 1997). Our first observations showed that generalized epilepsies and febrile seizure phenotypes were found in this form of familial epilepsy; however, later observations by ourselves and other groups demonstrated that a significant proportion of family members had focal epilepsies (Scheffer et al., 2000, 2007; Abou-Khalil et al., 2001; Ito et al., 2002). This evolution of our understanding prompted us recently to rename the syndrome “Genetic Epilepsy with Febrile Seizures Plus” (still GEFS+) to emphasize the genetic etiology of the epilepsy in these families and to remove the inference that focal epilepsy is not part of GEFS+ (Scheffer & Berkovic, 2008). Several ion-channel genes have mutations in GEFS+ families, adding molecular evidence that further strengthens the validity of clinical research observations (Helbig et al., 2008). In the absence epilepsies, a similar process of maturation in our understanding of these syndromes has occurred. The advent of video-monitoring allowed epileptologists to scrutinize the clinical features of absence seizures. Penry’s seminal work on the clinical features of absence seizures laid the ground work using this approach (Penry et al., 1975); fastidious studies by a host of epilepsy researchers have further informed our concepts (see studies referenced in Sadleir et al., 2008 and Panayiotopoulos commentary, 2008). Novel clinical observations are usually based on relatively few cases that generate insightful hypotheses, as in the seminal work of Panayiotopoulos over the years. This is the time-honored approach of clinical observation. The critical next step is to replicate and refine these observations in larger, independent groups of patients to determine whether the hypotheses stand up to the test. This takes syndromology to an evidence-based level (Berg & Blackstone, 2006). In the absence epilepsy syndromes, the study by Sadleir and colleagues has addressed some important questions raised in the literature (Sadleir et al., 2006, 2008). It examined absence seizures seen in the idiopathic generalized epilepsies (IGEs) in an untreated group of children presenting with staring spells. There are many definitions of the IGE syndromes, and investigators disagree about the fine detail of the syndromes, especially the borderline cases. To focus on more typical cases of a syndrome, the Sadleir study adopted definitions of the IGE syndromes based on the well-accepted ILAE 1989 Classification using pragmatic boundaries (ILAE, 1989). For example, childhood absence epilepsy (CAE) was defined by onset of seizures before 10 years of age and juvenile absence epilepsy (JAE) thereafter. Another oft-discussed example is whether myoclonic seizures can occur in JAE; many epileptologists use a pragmatic definition of juvenile myoclonic epilepsy (JME), whereby the presence of myoclonic seizures defines JME rather than JAE. There is no doubt that there are imperfections in these definitions, as JME can begin before the age of 8 years; however, this analysis allows a cleaner gestalt of the majority of patients presenting with each syndrome rather than the “overlap” cases. The argument that the initial diagnosis of the syndrome may be made in error is valid; however, it is likely that this happens only rarely, as the work of Berg et al. showed that specific syndrome diagnoses at onset were both sensitive and specific to diagnoses appreciated 2 years later (Berg et al., 2000). Within the IGEs, children may express one form of epilepsy (e.g., CAE) and later another related form (e.g., JME). This well-recognized evolution of one syndrome to another within the IGEs does not detract from the accuracy of the diagnosis of the initial syndrome. The key hypothesis tested by the Sadleir study was that clinical features of absence seizures are syndrome-specific and, therefore, aid in differentiating absence epilepsy syndromes. As with GEFS+, observations of relatively few cases led to hypotheses about syndromic correlates, for example, the theory that eye opening occurs earlier in CAE than in JME (Panayiotopoulos et al., 1989a,b). Evidence from the study of Sadleir and others (Sadleir et al., 2008) suggests this is not the case and that this feature may not reliably distinguish between these two syndromes. On the other hand, some observations do indeed stand the test of time, such as Penry’s finding that automatisms are more likely with longer duration of absence seizures (Penry et al., 1975) (Sadleir L, Scheffer I, Smith S, Connolly M, Farrell K, unpublished data), or that absence seizures are briefer in JME than in CAE (Panayiotopoulos et al., 1989a; Sadleir et al., 2008). In the end, we should not strive to achieve a specific result but to use valid, accepted methods that lead us to the most reliable result, one we hope is as close as possible to an elusive truth, whatever that may be. As researchers, we need to remain dispassionate about our findings and accepting of new data that challenge or even refute our previously held views of epilepsy syndromes, constantly but methodically revising and refining our understanding to make it more robust. What’s more, new observations make our task all the more exciting and intriguing and pose the challenge of taking the science of epileptology forward. In this way, our goal of helping our patients and understanding the neurobiology of the epilepsies will remain the foremost drivers of our research. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Competing interests: The authors have no competing interests to disclose.