Coexistence of Idiopathic Rolandic Epilepsy and CSWS in Two Families

Authors


Address correspondence and reprint requests to Dr. X. De Tiège at Department of Pediatric Neurology, ULB-Hôpital Erasme, 808 route de Lennik, 1070 Brussels, Belgium. E-mail: xdetiege@ulb.ac.be

Abstract

Summary: Purpose: To report two families combining benign childhood epilepsy with centrotemporal spikes (BCECS) and cryptogenic epilepsy with continuous spike–waves during sleep (CSWS) in first-degree relatives.

Methods: Clinical, EEG, and cerebral imaging data are described.

Results: Family 1: The proband was 3 years old at epilepsy onset. First seizures were convulsive, with centrotemporal spikes on EEG. At age 5 years, he had complex partial seizures, psychomotor regression, and centrotemporal CSWS. [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) showed left parietal hypermetabolism. After several antiepileptic drug (AED) trials, valproate (VPA) and ethosuximide (ESM) induced seizure remission, CSWS disappearance, and psychomotor improvement. Learning disabilities, however, persisted. Family history was remarkable for BCECS in his father. Family 2: The proband was 2 years old at epilepsy onset. First seizures were convulsive, with centrotemporal CSWS on EEG. Despite several AED trials including corticosteroids, focal negative myoclonia, atypical absences, and psychomotor regression occurred, leading to severe mental retardation. FDG-PET showed bilateral parietal hypermetabolism. Vagus nerve stimulator was implanted. Her family history was remarkable for BCECS in her father and febrile convulsions in infancy in her mother.

Conclusions: These data suggest the existence of a common genetic basis between BCECS and cryptogenic epilepsies with CSWS. The higher expression in patients with CSWS could be related to other genetic or acquired factors. These data suggest that these epileptic syndromes constitute edges of a continuum.

Benign childhood epilepsy with centrotemporal spikes (BCECS) is the most common epilepsy of childhood and is classified as idiopathic partial epilepsy (IPE). This age-related epileptic syndrome is considered to be of genetic origin (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Centrotemporal spike–waves (CTSs) that may be activated by sleep characterize the epileptiform activity of this syndrome (Commission on Classification and Terminology of the International League Against Epilepsy, 1989).

Epileptic syndromes with continuous spikes and waves during sleep (CSWS) are age-related epilepsies characterized by various cognitive dysfunction and seizure types that have the EEG pattern of CSWS as a common feature (De Negri et al., 1997; Veggiotti et al., 1999). This EEG pattern is defined by the presence of spike-and-wave discharges during ≥85% of non–rapid eye movement (NREM) sleep (Veggiotti et al., 1999). A minority of cases have been associated to cortical and/or thalamic lesions (symptomatic cases), whereas, in the majority of cases, the etiology is unknown (cryptogenic cases) (Veggiotti et al., 1999).

A common pathophysiologic background between BCECS and cryptogenic epilepsies with CSWS is suspected because these two syndromes are age related and display common EEG features. Intermediate forms have also been repeatedly described (Aicardi and Chevrie, 1982, De Negri, 1997).

We report two families characterized by the presence of well-documented BCECS and cryptogenic CSWS in first-degree relatives.

METHODS

Clinical, EEG, and cerebral imaging data of probands and fathers from two different families were reviewed. The father of family 1 was followed up in our Pediatric Neurology Department, and the father of family 2 provided us his complete medical files, including EEG samples. The diagnosis of CSWS in the probands was based on the presence of >85% of spike–waves during NREM sleep in at least three different sleep EEGs (Tassinari et al., 2000). Data of cerebral positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) were analyzed by using voxel-based analyses with a method previously described (De Tiege et al., 2004).

RESULTS

Family 1

The proband had an unremarkable medical history until age 3 years, when he had a nonfebrile nocturnal convulsive seizure. When 4 years old, he had two episodes of nocturnal convulsive seizures. EEG showed bilateral CTS. Valproate (VPA) treatment was initiated. One year later, convulsive seizures recurred, and his cognitive performance progressively declined (IQ = 50) together with behavioral deterioration (attention deficit and hyperactivity, impaired social contacts, and aggressiveness). Sleep EEG showed bilateral centrotemporal CSWS predominant on the left side. Levetiracetam (LEV) was then added to VPA and induced seizure remission with partial improvement in cognitive and behavioral disturbances (IQ = 70). At age 6 years, convulsive seizures recurred, and centrotemporal CSWS were again observed (Fig. 1). FDG-PET showed left parietal hypermetabolism (pcorrected < 0.05; Fig. 2). Cerebral magnetic resonance imaging (MRI) was normal. Clobazam (CLB) add-on induced seizure remission for 6 months. Then complex partial seizures recurred, and led to substitution of LEV by topiramate (TPM). Because of lack of efficacy and clinical intolerance, TPM and CLB were tapered off, and ethosuximide (ESM) was added to VPA. This treatment led to seizures and CSWS disappearance, with behavioral and cognitive improvement (IQ = 75). The patient was steered toward specialized teaching for children with learning disabilities.

Figure 1.

Family 1. Left: Sleep EEG of the proband performed at the age of 6 years, showing left centrotemporal continuous spike-waves during sleep (CSWSs) partially spreading to the right side. Right: Awake EEG of his father performed at the age of 6 years, showing right centrotemporal spike–waves (CTSs).

Figure 2.

Voxel-based analyses of [18F]fluorodeoxyglucose–positron emission tomography (FDG-PET) studies of the probands performed during the active phase of continuous spike–waves during sleep (CSWSs) by using statistical parametric mapping. Areas of abnormal metabolism are significant by comparison with a control group (pcorrected < 0.05) Left: FDG-PET of the proband of family 1 showing significant hypermetabolic area in the left parietal region. Middle and right: FDG-PET of the proband of family 2, showing significant hypermetabolic area in the parietal region bilaterally and significant hypometabolic area in the prefrontal and left orbitofrontal regions.

The proband's family history was remarkable for typical BCECS in his father, characterized by epilepsy onset at age 4 years, rare partial seizures (fewer than one per year), normal cerebral CT scan, and right CTS on awake EEG (12 EEG samples available from the ages 4–9 years; Fig. 1). He did not have any sleep EEG. He had been treated by a combination of phenytoin (PHT) and phenobarbital (PB) until adolescence. His psychomotor development had been normal without any history of psychomotor regression (IQ = 107). He works as a school teacher.

Family 2

The proband was age 2.5 years when she had two convulsive seizures. Her medical history was characterized by motor (walk at 20 months) and language (only 10 intelligible words at epilepsy onset) developmental delay. Cerebral MRI was normal. EEG showed bilateral CTS during awakening and bilateral centrotemporal CSWS during NREM sleep (Fig. 3). Despite VPA treatment, complex partial seizures occurred. From age 3–5 years, she had three episodes of psychomotor regression characterized by axial hypotonia, ataxia, inability to walk alone, language and neuropsychological regression associated with focal negative myoclonia, and atypical absences. Bilateral centrotemporal CSWS were repeatedly observed on sleep EEG. Voxel-based analysis of cerebral FDG-PET data showed bilateral parietal hypermetabolism with frontal hypometabolism (pcorrected < 0.05; Fig. 2). After multiple treatment failures [CLB, TPM, hydrocortisone, LEV, sulthiame (SLT), ESM, felbamate (FBM), carbamazepine (CBZ), and intravenous immunoglobulin], a combination of VPA, LTG, and clonazepam (CZP) induced partial seizure control and psychomotor improvement. Vagus nerve stimulation was started because of episodic seizure recurrence and CSWS persistence. Because of severe mental retardation (IQ = 30), she was steered toward specialized teaching.

Figure 3.

Family 2. Left: Sleep EEG of the proband performed at the age of 2.5 years, showing bilateral centrotemporal continuous spike–waves during sleep (CSWS) predominant on the left side. Right: Awake EEG of his father performed at the age of 11 years, showing asynchronous left rolandic and parietal spikes.

The proband's familial history was remarkable for BCECS in her father, characterized by epilepsy onset at age 5 years, rare simple nocturnal partial seizures (fewer than one per year) until the age of 11 years, normal cerebral CT, and multifocal spikes (bilateral asynchronous CTS, parietooccipital spikes) on awake EEG (26 EEGs available from ages 8–20 years; Fig. 3). A sleep EEG performed at age 11 years showed bilateral asynchronous CTS not activated by sleep. He had been treated with VPA until age 11 years. Because of nocturnal seizure recurrence and hyperammonemia, VPA was switched to CBZ until adolescence. He had had learning disabilities without any history of psychomotor regression and had received specialized teaching (IQ = 78). His profession is workman. The proband's mother had simple febrile seizures during infancy. Her paternal grandmother had episodic nocturnal seizures between ages 4 and 15 years. Her paternal great-grandfather had uncharacterized epilepsy.

DISCUSSION

Two families associating BCECS and epileptic syndrome with cryptogenic CSWS in first-degree relatives are reported.

Both probands had epilepsy with CSWS according to the classification of the International League Against Epilepsy (ILAE) (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Their epileptic syndrome were, indeed, characterized by different pharmacoresistant seizure types without tonic seizures, episodes of psychomotor regression related to the presence of CTS diffusing to the hemisphere during >85% of NREM sleep and poor neuropsychological evolution (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). The focal increase in glucose consumption in the area of interictal spiking at the time of CSWS, which has not been reported in BCECS, supported the diagnosis of epilepsy with CSWS (Van Bogaert et al., 1998; De Tiege et al., 2004). The severity of the epileptic syndromes of both probands contrasts with the benign evolution of the epileptic disorder in their fathers, which corresponded to BCECS according to the ILAE classification (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). The occurrence of learning disabilities in the father of family 2, which have been repeatedly reported in BCECS (Deonna et al., 2000), can nevertheless be considered as atypical in this syndrome.

To the best of our knowledge, this is the first report of well-documented BCECS and CSWS in first-degree relatives. Indeed, a great lack of detailed data is available on epilepsy or CTS incidence in relatives of children with CSWS (Tassinari et al., 2002). We found only three studies dealing with this topic. The first one addressed the genetic background of 147 children with focal sharp waves (Doose et al., 1997). In a subgroup of 15 children with CSWS or intermediate forms, the incidence of seizures in 125 relatives was 4% (Doose et al., 1997). In the second study including 43 children with atypical benign partial epilepsy (ABPE), convulsive seizures were reported in only three fathers (Doose et al., 2001). The third study compared the clinical and EEG characteristics of 16 patients with IPE who subsequently developed epilepsy with CSWS with those of 25 children with typical IPE (Saltik et al., 2005). In that study, Saltik et al. found a history of epilepsy in 37.5% of the relatives of children with CSWS, a proportion 3 times higher than in the group of children with typical BCECS (Saltik et al., 2005). In those three studies, family data were not reported in detail, and seizure types or epileptic syndromes were not specified (Doose et al., 1997, 2001; Saltik et al., 2005).

Our data support the existence of a common genetic basis in cryptogenic CSWS and BCECS. The existence of families with asymptomatic carriers of CTS and typical or atypical rolandic epilepsy in the same generation also supports this assumption (Doose and Baier, 1989, Doose et al., 2001). In the families we here report, the difference of severity in the probands and their fathers could be related to a higher expression of identical genetic traits in both probands, facilitated by other genetic factors (Doose and Baier, 1989, Doose et al., 2001, Saltik et al., 2005). The occurrence of other epilepsy cases in the second family supports the concept of additive effects of different genetic traits on the phenotypic expression of the epileptic disorders (Saltik et al., 2005). Interestingly, a previous study described a family with rolandic epilepsy and speech dyspraxia characterized by clinical anticipation, probably related to an abnormal expansion of unstable triplet (Scheffer et al., 1995). This indicates that diverse mechanisms of inheritance might explain the difference of severity of the epileptic disorders observed in the two families here reported.

Twins studies highlight the fact that nongenetic factors are involved in the pathophysiology of CSWS as well as BCECS (Vadlamudi et al., 2004). Indeed, the concordance of monozygotic pairs of children with Landau–Kleffner syndrome or BCECS is very low (Feekery et al., 1993, Vadlamudi et al., 2004). The etiology of these epileptic disorders is therefore most probably multifactorial (Vadlamudi et al., 2004).

In conclusion, the data presented suggest that among the heterogeneous group of epilepsies with CSWS, a subgroup of patients belong to a continuum with common genetic predisposition and clinical presentations ranging from asymptomatic carriers of CTS to cryptogenic epilepsies with CSWS.

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