Early onset absence epilepsy with onset in the first year of life: A multicenter cohort study

Authors


Summary

Purpose

Absence epilepsy with onset before age 4 years, or early onset absence epilepsy (EOAE), has been rarely reported, and children with onset in the first year of life are considered almost exceptional. We aimed to report the clinical and electrophysiologic features of a cohort of children with absence epilepsy starting within the first year of life.

Methods

This was a multicenter study including patients with absence epilepsy starting within the first year of life and identified over a 20-year period (1991–2011).

Key Findings

We identified 16 patients with absence epilepsy starting within the first year of life with a mean follow-up of 6.4 years. Mean age at seizure onset was 10.3 ± (standard deviation)1.4 months (range 8–12). Two patients experienced rare tonic–clonic seizures that started later than the absences. None of the subjects had episodes of absence status epilepticus. Eleven subjects were seizure-free with the first antiepileptic drug. In eight children, therapy was withdrawn after a mean 3.2 years of treatment. None evolved into a different form of idiopathic generalized epilepsy. SLC2A1 gene analysis in 12 children (75%) failed to reveal glucose transporter 1 deficiency.

Significance

EOAE, including patients with onset within the first year of life, should be no more considered a distinct idiopathic generalized epilepsy (IGE) syndrome, as it shows electroclinical features, response to therapy, and prognosis similar to childhood absence epilepsy. Moreover, early age of onset is not predictive of GLUT-1 deficiency and genetic analysis may be therefore avoided in patients meeting strict inclusion criteria.

Childhood absence epilepsy (CAE) is an epileptic syndrome classified among idiopathic generalized epilepsies (IGEs), with seizure onset between 4 and 9 years, and which manifests with transient impairment of consciousness associated with bilateral, regular, symmetrical, and generalized spike-waves on electroencephalography (EEG; Panayiotopoulos, 2008). Absence epilepsy with onset before age 4 years or early onset absence epilepsy (EOAE) has been rarely reported as single cases (De Marco, 1980; Cavazzuti et al., 1989) or in small series (Shahar et al., 2007; Caraballo et al., 2011; Farooque et al., 2011; Giordano et al., 2011; Verrotti et al., 2011), and it has been suggested that about 10% of the patients have mutation in the SLC2A1 gene, which underlies glucose transporter 1 (GLUT-1) deficiency (Suls et al., 2009; Arsov et al., 2012). Absence epilepsy with onset in the first year of life is considered almost exceptional (Cavazzuti et al., 1989). This multicenter study reports the clinical data of a cohort of children with absence epilepsy starting within the first year of life.

Methods

Clinical data of patients with absence seizures referred from different Italian epilepsy centers were reviewed over a 20-year period (1991–2011). The study was approved by the ethics committee of each institution. Inclusion criteria were the following: (1) seizure onset in the first year of life; (2) typical absence seizures captured at EEG recordings accompanied by bilateral, regular, symmetric, >2.5 cycles/second (c/s) generalized spike-waves; and (3) normal development and unremarkable neurologic examination at onset. Subjects were not eligible if they had at least one of the following exclusion criteria: (1) other seizure types (e.g., myoclonic, atonic, tonic) before, during, or after the absences; (2) incomplete impairment of consciousness during spike-wave discharges on EEG, or photic or other sensory precipitation of the absences. Family and personal history of febrile seizures or epilepsy, neurologic examination, drug treatment, and intellectual functioning were reviewed from clinical charts of each center. Mutation analysis of SLC2A1 was performed by direct sequencing on genomic DNA when informed consent signed by patients or their parents was given. Statistical analysis was carried out by using the SSPS 16.0 version, WinWrap (SPSS Inc., Chicago, IL, U.S.A.).

Results

A total of 16 (8 male) patients fulfilled the inclusion criteria. Their data are summarized in Table 1. Patients 8 and 9 were sisters. The father of patients 4 and 13 had febrile seizures. The mother of patient 4 had CAE; and the brother of patient 16 was affected by rolandic epilepsy. None of the patients had febrile seizures. Mean age at seizure onset was 10.3 ± (standard deviation) 1.4 months (range 8–12). By definition, all children had normal development and unremarkable neurologic examination. They had frequent, daily absences (i.e., pycnolepsy) with EEG correlate of >2.5 c/s generalized spike-waves (Fig. 1). Patients 2 and 6 experienced rare tonic–clonic seizures starting later than absences. None of the subjects had episodes of absence status epilepticus. Eleven patients (68.7%) were seizure-free with the first antiepileptic drug (AED), which was valproate in all cases. In the other four cases, the introduction of one or two additional AEDs (ethosuximide, levetiracetam, or clobazam) was needed to control absences. Follow-up duration ranged from 3 to 17 years (mean 6.4 ± 4.4). At the last evaluation, all individuals had normal awake or sleep EEG and displayed normal intellectual functioning. None of them evolved into a different form of IGE. Eight children were still on therapy, whereas in the other eight individuals, AEDs had been withdrawn after a mean 3.2 years of period of treatment with no seizure recurrence or reappearance of EEG abnormalities. Mutation screening of SLC2A1 was performed in 12 cases (75%), but no mutation was identified.

Table 1. Clinical characteristics of the 16 patients with absence seizures with onset in the first year of life
Patient ID/sex/age (years)Family historyAbsence onset (months)Age at seizure freedomTCS (age)AEDsFollow-up (years)AED treatment duration (years)SLC2A1 testing
  1. TCS, tonic–clonic seizures; CAE, childhood absence epilepsy; FS, febrile seizures; VPA, valproate; ETS, ethosuximide; LEV, levetiracetam; CLB, clobazam; ND, not done; EOAE, Early onset absence epilepsy.

1/M/12112 yearsNoVPA+ETS11OngoingNegative
2/F/382 yearsYes (13 month)VPA+ETS22Negative
3/F/1893 yearsNoVPA177Negative
4/F/10CAE (mother), FS (father)96 yearsNoVPA5OngoingND
5/M/6115 yearsNoVPA+LEV5OngoingNegative
6/M/493 yearsYes (24 month)VPA+ETS+CLB2OngoingNegative
7/M/151014 monthsNoVPA132Negative
8/F/12EOAE (sister)812 monthsNoVPA10OngoingNegative
9/F/3EOAE (sister)1012 monthsNoVPA2OngoingNegative
10/M/9124 yearsNoVPA74ND
11/M/9114 yearsNoVPA73Negative
12/F/7124 yearsNoVPA63Negative
13/M/2FS (father)104 yearsNoVPA2OngoingNegative
14/M/41116 monthsNoVPA3OngoingNegative
15/F/18Rolandic epilepsy (brother)1213 monthsNoVPA83ND
16/F/51216 monthsNoVPA32ND
Figure 1.

EEG recordings of patient 6 have daily absences from age 9 months and showing >2.5 c/s generalized spike-wave discharges while awake (up) and during sleep (down).

Discussion

Absence seizures and related epileptic syndromes are still a challenge despite significant progress made in their pathophysiology, genetics, clinical, and video-EEG aspects. From the clinical point of view, even if IGE syndromes featuring absence seizures are a continuum, their differentiation has significant prognostic and management implications (Panayiotopoulos, 2008). EOAE has been previously considered a distinct syndrome within the spectrum of IGE showing electroclinical features, response to therapy, and prognosis that are similar but not identical to those in CAE (Shahar et al., 2007; Caraballo et al., 2011; Farooque et al., 2011; Giordano et al., 2011; Verrotti et al., 2011). In the majority of cases, a good AED response with rapid disappearance of seizures is obtained with monotherapy, whereas in some children, add-on of another AED is needed to obtain seizure control (Shahar et al., 2007; Caraballo et al., 2011; Farooque et al., 2011; Giordano et al., 2011; Verrotti et al., 2011).

EOAE in the first year of life is an even more rare condition, and there are very few long-term outcome data. During the past 10 years, 14 cases have been reported by different authors (Guerrini et al., 2002 [four cases], Shahar et al., 2007 [one case], Muhle et al., 2010 [one case], Verrotti et al., 2011 [one case], Giordano et al., 2011 [three cases], Kobayashi et al. 2011 [one case], Farooque et al., 2011 [two cases], Asadi-Pooya et al., 2012 [one case]). However, most of these patients show additional neurologic features other than absence epilepsy, including paroxysmal exertional dyskinesias, mental delay/psychiatric comorbidities, facial dysmorphisms, and drug-resistant seizures (Guerrini et al., 2002; Muhle et al., 2010; Farooque et al., 2011; Kobayashi et al., 2011).

The present study includes the largest series of children with absence seizures starting within the first year of life. Family history of febrile seizures or idiopathic epilepsy was present in a minority of patients. In all subjects absences started after 8 months of life, and tonic–clonic seizures occurred in only two individuals. Valproate monotherapy was effective in more than two thirds of the subjects, and all individuals displayed normal intellectual functioning at the last evaluation, in accordance with previously reported EOAE series (Shahar et al., 2007; Giordano et al., 2011; Verrotti et al., 2011). None evolved into a different form of IGE.

It has been suggested that up to 10% of EOAE patients have mutation in the SLC2A1 underlying GLUT-1 deficiency, which cannot be diagnosed on clinical grounds (Suls et al., 2009; Arsov et al., 2012). However, such patients usually show drug-resistant absences or additional neurologic signs, including slight/mild ataxia, intellectual disability, movement disorders, or microcephaly.

None of the 12 tested subjects from the present series showed SLC2A1 mutations, confirming the view that early age of onset is not predictive of GLUT-1 deficiency and that genetic analysis may be avoided for patients selected with strict inclusion criteria (i.e., absence epilepsy without associated neurologic features) (Giordano et al., 2011; Verrotti et al., 2011; Agostinelli et al., 2013; Verrotti et al., 2013). A possible exception can be represented by IGE families with autosomal dominant pattern of inheritance and patients featuring absence epilepsy with variable age of onset (Striano et al., 2012).

In summary, clinicians should be aware that absence epilepsy may start even in the first year of life and that these patients may show good prognosis, both in term of seizure outcome and cognition. Whether these represent a continuum with other IGE syndromes or they are genetically the same remains a matter of research. Finally, it should be reminded that absence seizures can be observed also in other epilepsy syndromes, such as myoclonic epilepsy of infancy, Jeavons syndrome, and epilepsy with myoclonic absences (Caraballo et al., 2011). Further studies are needed to better characterize these epileptic syndromes as well as to identify prognostic factors having significant implications for management.

Acknowledgments

We would like to thank the Genetic Commission of the Italian League Against Epilepsy (LICE). We would like to thank Dr. Bernardo Dalla Bernardina, Maria Paola Canevini, Federico Vigevano, and Federico Zara for their active participation in case collecting and patient selection.

Disclosures

The authors have no conflicts of interests. No financial support has been received for this study. There is no financial relationship to disclose for all the authors. 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.

Ancillary