Typical absences seizures (TAS) are generalized seizures of sudden onset and termination, usually lasting for seconds up to minutes. The main clinical manifestation is impairment of consciousness with concomitant bilateral, regular, symmetric, and generalized 3–4 Hz spike-waves on electroencephalography (EEG) (Berg et al., 2010). These seizures usually occur in the context of idiopathic (genetic) generalized epilepsies (IGE), such as childhood absence epilepsy (CAE), epilepsy with myoclonic absences, juvenile absence epilepsy, and juvenile myoclonic epilepsy (Panayiotopoulos, 2008).
Onset of TAS is frequently limited between 4 and 9 years of age and the youngest age has been set at 3 years (Panayiotopoulos, 2008). Nevertheless, clinical series of children with TAS before 3 years of age have been reported (Shahar et al., 2007; Caraballo et al., 2011; Giordano et al., 2011; Verrotti et al., 2011; Agostinelli et al., 2013). In the first 3 years of life, TAS may occur in different epileptic syndromes, such as CAE of early onset, benign myoclonic epilepsy of infancy, eyelid myoclonia with absences, and epilepsy with myoclonic absence (Caraballo et al., 2011). Recently, we showed that the application of strict criteria for CAE, suggested by Panayiotopoulos, leads to a group of children showing homogeneous electroclinical features with response to therapy and prognosis, similar but not identical to CAE (Giordano et al., 2011; Verrotti et al., 2011; Agostinelli et al., 2013). In contrast, some authors, using broad inclusion criteria, observed a variable epilepsy outcome, ranging from complete control with first antiepileptic drug (AED) monotherapy to severe refractoriness despite polytherapy (Suls et al., 2009; Arsov et al., 2012). More importantly, mutations in the SLC2A1 gene encoding the glucose transporter type 1 (GLUT1), have been found in >10% of children (Suls et al., 2009; Arsov et al., 2012).
The purpose of this multicenter study was to investigate if patients with TAS starting in the first 3 years of life but otherwise conformed to CAE definition had a different electroclinical course than those not fulfilling CAE criteria. Occurrence of SLC2A1 mutations and comparisons between children with different AED initial responses were evaluated. Another goal was to analyze multiple electroclinical factors to identify patients who had the strongest risk of poor prognosis with seizure relapse during follow-up.
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- Appendix 1
In this study, we used a strict definition of P-EOAE because children had onset of absence seizures within the first 3 years of life, but otherwise conformed to CAE criteria proposed by Panayiotopoulos (Panayiotopoulos, 2008). These criteria are different from those previously used in the context of GLUT-1 deficiency syndrome, which included patients with onset of absences before 4 years of age, generalized spike-waves (>2.5 Hz) on EEG, no evidence of secondary cause for epilepsy, and absence of atonic–tonic seizures (Suls et al., 2009; Arsov et al., 2012).
We found significant clinical differences between P-EOAE and NP-EOAE to justify a syndrome-based definition. In P-EOAE the absences started at an older age and were better controlled by AEDs with shorter time and less 6-month EEG abnormalities than in NP-EOAE. At last contact, longer remission with shorter duration of treatment and less frequent relapses were observed in P-EOAE compared to NP-EOAE. In contrast to the latter, children with P-EOAE did not show any other seizure types, abnormal brain MRI, and SLC2A1 mutations. Reasonably, in patients with newly suspected P-EOAE who are in accordance with our proposed criteria, it is not advisable to assess the SLC2A1 gene mutations.
Although TAS are considered the paradigm seizure type of IGE, they may occasionally be symptomatic, and associated with a known disorder of the central nervous system (Ferrie et al., 1995; Panayiotopoulos, 2001). These symptomatic TAS may be caused by focal or diffuse lesions (Ferrie et al., 1995). The mesial surfaces of the frontal lobe are the most likely brain locations to generate TAS in symptomatic cases (Panayiotopoulos, 2001). TAS has also been reported as the result of subependymal heterotopia (Raymond et al., 1994). In line with these observations, we observed in our series brain imaging abnormalities, such as subcortical focal hyperintensity of the frontal lobe, cortical dysplasia, gray matter heterotopia, and abnormalities of white matter signal. The fact that symptomatic (structural-metabolic) etiologies (i.e., brain abnormalities and GLUT1 deficiency) were observed only in children with NP-EOAE and not in those with P-EOAE was probably the cause of their worse prognosis and perhaps illustrates the natural course of epilepsy. In these patients a poor clinical evolution started after 12 months of follow-up and treatment was not effective in children received polytherapy (three AEDs) because of high rate of recurrence. The favorable and improving outcome in children with P-EOAE who became seizure-free with AED monotherapy (67.5%) or bitherapy (32.4%) could have been the result of treatments, although many patients withdrew without subsequent relapses. Considering these findings, treatment does not seem to have a major impact on the outcome of epilepsy. In accordance with hypothesis of Shinnar and Berg, (1994), the natural course of epilepsy and the underlying etiology better explain our results, with P-EOAE being short-lived and NP-EOAE having a designated poor outcome.
Application of our strict criteria for P-EOAE leads to a group of patients with homogeneous disease characteristics and prognosis, independent of fast AED response. In fact, when we compared children who responded to monotherapy and those who responded to bitherapy, similar demographic and electroclinical aspects were shown. As might be expected, patients treated with two AEDs, had seizures for a longer period and received smaller LTG doses than those treated with two AEDs. Difference in LTG dose values can be due to a pharmacodynamic beneficial effect of small LTG doses when added to VPA, which is the first-line AED most frequently used in our patients on bitherapy. These results are in line with those that we reported previously (Giordano et al., 2011; Verrotti et al., 2011; Agostinelli et al., 2013).
Conversely, in the group that did not meet Panayiotopoulos's criteria, more differences emerged between patients with initial response to monotherapy, bitherapy, and tritherapy. These differences indicate a heterogeneous group of epilepsies, including both patients who had a poor electroclinical prognosis as more associated with symptomatic etiologies (i.e., brain abnormalities and GLUT1 deficiency) and those who had an intermediate outcome between P-EOAE and symptomatic forms of NP-EOAE. Children with this intermediate outcome responded well to monotherapy or bitherapy, and showed myoclonic features during the active stage of epilepsy. This category may include some well-defined epileptic syndromes, such as the benign myoclonic epilepsy of infancy, eyelid myoclonia with absences, and myoclonic absence epilepsy. This is in line with the results provided by Caraballo et al. (2011).
At the end of follow-up, 62.2% of our cohort continued AEDs, not only those who relapsed, but also a considerable number of patients in remission. The proportion of subjects continuing treatment was lower in P-EOAE (54.1%) than in NP-EOAE (74.0%). Differences in etiology, length of initial absence control, and relapses during follow-up could explain this.
Although, brain MRI and EEG data and parameters of early seizure control were associated with outcome measurement, in the final multivariate analysis only Panayiotopoulos's criteria remained significant. Indeed, children without strict Panayiotopoulos's criteria had 2.134 times the odds of having relapse during the 36-month follow-up compared to patients who met Panayiotopoulos's criteria.
In conclusion, this study demonstrates that differences in electroclinical features and outcomes between patients with P-EOAE and NP-EOAE may be sufficient to delineate distinct subsyndromes within children presenting early onset absences. Patients who meet our modified Panayiotopoulos's criteria have a favorable course of epilepsy, whereas those not presenting them have a poor outcome with high risk of relapse during follow-up. Early onset absences not conforming to our strict diagnosis are part of epileptic disorders secondary to brain abnormalities and GLUT1 deficiency, as well as some well-defined epileptic syndromes, such as the benign myoclonic epilepsy of infancy, eyelid myoclonia with absences, and myoclonic absence epilepsy. NP-EOAE associated with symptomatic etiologies shows a poorer electroclinical prognosis than that reported in the context of well-defined epileptic syndromes.
Patients with EOAE are probably more frequent than we previously considered, and they should be better recognized and studied.