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Typical absence seizures and related epileptic syndromes: Assessment of current state and directions for future research

2008; Wiley; Volume: 49; Issue: 12 Linguagem: Inglês

10.1111/j.1528-1167.2008.01777.x

1528-1167

C. P. Panayiotopoulos,

Neonatal and fetal brain pathology

[In this section, we present a lead paper followed by a set of comment articles that have been invited by the editors. Our goal is to present different or opposing views on topical issues. Articles and comments are commissioned in the spirit of encouraging discussion and debate in a format that will stimulate thought and further research.] For myself I shall be well satisfied if I have made it appear probable to you that there does exist a form of epilepsy in children which is distinguishable by its clinical features and in which the prognosis is always good Adie (1924) differentiating “pyknolepsy” (syndrome) from “petit mal” (seizures) This commentary outlines clinical and electroencephalography (EEG) aspects of typical absence seizures (TAS) and related epileptic syndromes in order to identify areas of consensus as well as areas of uncertainty that may indicate directions for future research. This may also assist the International League Against Epilepsy (ILAE) Commission, which is currently working on establishing scientifically rigorous criteria for the identification of specific epileptic seizures and syndromes using an evidence-based approach (Engel, 2006). Relevant ILAE definitions and classifications are shown in Table 1. TAS and related epileptic syndromes were thoroughly assessed by leading clinicians and researchers in this area during a 3-day symposium in 1994 in London (Duncan & Panayiotopoulos, 1995). Consensus was achieved in the definition and semiology of TAS and controversies in their syndromic classification comprehensively debated (Reynolds et al., 1995). The report by Sadleir and colleagues (Sadleir et al., 2008) and its related predecessor on childhood absence epilepsy (CAE) (Sadleir et al., 2006) is assessed in the context of this debate. TAS are generalized seizures of sudden onset and termination, lasting for seconds. They are fundamentally different from other seizures and they are pharmacologically unique (Panayiotopoulos, 2005a). TAS have two requisite components: Clinically, the transient impairment of consciousness (TIC) (absence) EEG generalized >2.5 Hz spike- or polyspike-slow wave discharges (S-PWD). TAS usually occur in the context of idiopathic generalized epilepsies (IGE). The prefix “typical” is to differentiate them from atypical absences rather than to characterize them as “classical” or characteristic of any particular syndrome. Atypical absence seizures occurring in the context of mainly symptomatic epilepsies and with slow 2.5 Hz S-PWD, which are often of higher amplitude in the anterior regions (Fig. 1, A–K). By consensus, spike-wave frequency is higher than 2.5 Hz, mainly 3–4.5 Hz, but there are no recommendations on how these measurements should be made. Frequency is usually variable and faster in the first second (opening phase), becomes more regular and stable in the subsequent 3 s (initial phase), and slows down towards the terminal phase of longer S-PWD (Fig. 1) (Panayiotopoulos et al., 1989b). This is why our practice is to estimate mean frequency of the initial phase of S-PWD and not at the first second of S-PWD used by other authors (Holmes et al., 1987; Sadleir et al., 2006). S-PWD also show significant qualitative variations that are clinically significant when examined systematically; they may be fragmented, multiple spikes may predominate, and the relationship between spike/multiple and slow wave fluctuates (Fig. 1). Duration is easy to measure and commonly is from 3 to 30 s. Hyperventilation induces TAS in nearly all untreated patients. Intermittent photic stimulation may precipitate or facilitate S-PWD in any type of TAS (Fig. 1C, 1J, and 1K); eyelid myoclonia is a common clinical accompaniment. Generalized >2.5 Hz S-PWD is the EEG marker of TAS but may also be clinically silent or manifest with symptoms other than TIC (Fig. 1G) (Dalby, 1969; Genton, 1995; Koutroumanidis & Panayiotopoulos, 2008). Sadlier and coworkers (2006, 2008) define as absence seizure any type of >2.5 Hz S-PWD associated with clinical signs even if this is not associated with TIC. However, the latter could be either TAS with undetectable TIC (which is a matter of methodological sensitivity) or other that TAS epileptic seizures (Fig. 1G). The syndromic classification of IGE with TAS is controversial (Reynolds et al., 1995). One view is that all presentations are one disease or a biological continuum (Berkovic et al., 1987). Another view, which we support, is that IGE with TAS comprise distinct epileptic syndromes, four of which are recognized by the ILAE. These are childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), epilepsy with myoclonic absences (MAE), and juvenile myoclonic epilepsy (JME) (Tables 1 and 3). CAE, first described in the pre-EEG era by Adie (1924) as pyknolepsy, manifests with numerous severe TAS and good prognosis as subsequently confirmed with EEG, video EEG and long follow-up studies (Loiseau & Panayiotopoulos, 2004). There remain many areas of uncertainty of what is CAE. The ILAE broadly defines it as a syndrome with frequent (several to many per day) and severe absences (see ILAE definition of TAS), school age at onset (peak at 6–7 years), and common remission (Table 1). Exclusion criteria have been introduced (Loiseau & Panayiotopoulos, 2004). The ILAE, by accepting MAE and JME as separate syndromes, probably exclude myoclonic TAS and mild TAS from CAE (Commission, 1989). It is by this logic that EMA (which are primarily myoclonic) may also be an exclusion criterion. Further, by accepting reflex TAS as a distinct category, the ILAE indicates that these too may not be part of CAE. That perioral myoclonia or single violent jerks occurring in the course (not at onset) of TAS is an exclusion criterion may be debatable; however, their presence indicates worse prognosis (Panayiotopoulos, 2007a). The same applies for multiple spikes and fragmented S-PWD that also indicate a bad prognosis, coexistent myoclonic jerks, or generalized tonic–clonic seizures (GTCS) (Panayiotopoulos et al., 1989b; Fakhoury & Abou-Khalil, 1999). A simplistic but unsatisfactory practice is to label as CAE any child with onset of daily TAS at ≤10 years and to as early as 2 years (Sadleir et al., 2006). The 10 years of age cut off is arbitrary and not a decisive “gold standard” to define what is and what is not CAE. Further, TAS of recognized syndromes, such as MAE or JME, may start before that age, and TAS of early childhood onset ( 2.5 Hz S-PWD to supplement previous reports cited above. However, attempts to expand this beyond a pure semiological study and the resultant conclusions are premature because of the lack of any follow-up compounded with questionable definitions and arbitrary diagnostic categorizations that, contrary to their assertion, do not comply with the ILAE definitions: CAE is not synonymous with TAS starting at age ≤10 years, myoclonic jerks are not an exclusion criterion for JAE, and TAS of JME were studied only when onset was at ≥11 years, which means that JME subjects with onset of TAS between 8–11 years were either absent or misplaced in CAE. For a statistical analysis to give meaningful results, the conditions assessed should be thoroughly examined and properly defined, which does not appear to be the case in the current report of Sadleir et al. (2008). Publication of the progress of the study population first presented between 1992–1997 may resolve important issues assessed in this commentary. Most patients classified as CAE should now be in remission or will have developed features of other IGE-TAS syndromes with TAS starting in childhood as per the Table 3. Until then, there is a wealth of knowledge gathered over many years in thorough studies that may help to shed light on these issues. These must be objectively and fully assessed, paying particular attention to important differences between individual reports in patient populations, prospective or retrospective character, length of follow-up, and other study parameters. Clustering them together as in the reports of Sadleir et al. (2006, 2008) weakens their contribution and promotes erroneous assumptions. TAS and related epileptic syndromes are a formidable challenge despite significant progress made in their pathophysiology, genetics, clinical, and video EEG aspects. Their classification is a work in progress, and we should all remain open to future refinements. We are in need of thorough prospective studies with precise definitions and targets. Significant evidence of the processes underpinning these diseases may emerge, and our old notions discarded, in the best spirit of unbiased work with an open-minded and dispassionate scientific decorum. From the clinical point of view, even if IGE syndromes with TAS were a continuum or genetically the same (which is unlikely considering current knowledge in animals and humans), their differentiation has significant prognostic and management implications. This may sometimes be difficult in clinical practice, but it is not unusual in medicine where diseases are identified on the sole basis of scientific evidence. In epilepsies, current good practice recommendations promote an epileptic syndrome diagnosis, and seizure-syndrome treatment. This progress has been achieved through considerable debates against the previous detrimental lumping of all of them in “epilepsy.” Physicians have been perceptive to this progress, and we should be encouraged to this optimal practice. I am grateful to eminent colleagues who have helped me with their experiences, thoughts, and their critical review of this commentary, particularly Dr. R.A. Grünewald, who also assisted me in editing the various drafts to its final form. Conflict of interest: I confirm that I have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The author has no conflicts of interest to disclose. The author has a paid consultancy with UCB Pharma S.A., and an unrestricted educational grant for a series of a multivolume edition of The Educational Kit on Epilepsies.