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Treatment of malignant migrating partial epilepsy of infancy with rufinamide: report of five cases Volume 13, numéro 1, Mars 2011

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  • Treatment of malignant migrating partial epilepsy of infancy with rufinamide: report of five cases

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epd.2011.0406

Auteur(s) : Martina Vendrame1,2, Annapurna Poduri1, Tobias Loddenkemper1, Gerhard Kluger3, Giangennaro Coppola4, Sanjeev V Kothare1 Sanjeev.Kothare@childrens.harvard.edu

1 Epilepsy and Clinical Neurophysiology, Children's Hospital Boston, Boston

2 Epilepsy and Clinical Neurophysiology, Boston University, Boston, MA, USA

3 Epilepsiezentrum für Kinder und Jugendliche, Klinik für Neuroplsquädiatrie und Neurologische Rehabilitation, Vogtareuth, Germany

4 Clinic of Child Neuropsychiatry, Second University of Naples, Naples, Italy

Correspondence. S.V. Kothare, Children's Hospital Boston, Fegan 9, 300 Longwood Ave, Boston, MA 02115, USA

The syndrome of malignant migrating partial epilepsy of infancy (MMPEI) is characterized by early onset of multiple seizure types emanating from different brain locations across time, highly pharmaco-resistant seizures, and overall poor prognosis (Coppola, 2009; Coppola et al., 1995). So far, antiepileptic drugs (AEDs) which have shown partial seizure control in MMPEI have included potassium bromide, stiripentol with clonazepam, and levetiracetam (Okuda et al., 2000; Coppola et al., 2007; Hmaimess et al., 2006; Perez et al., 1999).

Rufinamide (RUF) is a relatively new AED, approved by the Food and Drug Administration (FDA) in November 2008 for use as add-on therapy in Lennox-Gastaut syndrome in adults and children (four years of age and over) (Glauser et al., 2008; Biton et al., 2005; Palhagen et al., 2001). Here, we describe the effect of RUF in five cases of MMPEI.

Case reports

Patient 1 was a 26-month-old boy who developed seizures from two weeks of age. Semiology included clonic and/or tonic jerks of one limb, twitches of the eyelids, and chewing movements, along with desaturations and short apnoeas. Multiple electroencephalograms (EEGs) showed electro-clinical seizures from the right and left fronto-central and temporal areas, and interictal right temporo-occipital discharges. Brain magnetic resonance imaging (MRI) was normal. Seizures occurred in one to five clusters about one to two times per week. RUF was added to levetiracetam and topiramate at a starting dose of 100 mg/day (10 mg/kg/day). Because of some improvement in seizure frequency, RUF was gradually increased to a maximal dose of 600 mg/day (60 mg/kg/day). After four months, rare brief seizures were reported (one per month) without desaturations and apnoeas, with no side effects of RUF. Topiramate was successfully tapered during three months of subsequent follow-up. Maximal length of follow-up after initiation of RUF was seven months.

Patient 2 was a 25-month-old girl with tonic movements including eye deviation to one side and apnoeas with desaturation from the age of two months. Her EEGs showed electro-clinical seizures from the right fronto-temporal and left temporo-occipital areas, and her MRI was normal. Seizure frequency was about 7-10 seizures per week. RUF was added to levetiracetam and lamotrigine at a starting dose of 100 mg/day (10 mg/kg/day). Because of no observed benefit, RUF was titrated to 800mg/day (75 mg/kg/day). After six months, seizure frequency decreased to two to three brief seizures per week, with no apnoeas or desaturations and no side effects. There was no change in medication during this period. Maximal length of follow-up after initiation of RUF treatment was six months.

Patient 3 was a 30-month-old boy with multiple seizures per week from the age of three months. Seizures were described as staring with eyelid twitching and tonic-clonic movements (see video sequence). EEGs showed interictal multifocal discharges (figure 1) and seizures emanating from bilateral independent foci, spreading over to the contralateral hemisphere (figure 2). RUF was added to lamotrigine, increased to a maximal dose of 100 mg/day (10 mg/kg/day) and discontinued after two weeks because of side effects (vomiting). No change in seizure frequency was observed during this period.

Patient 4 was a 41-month-old girl with multiple seizure types from the age of 3.5 months. Multiple EEGs showed numerous seizures starting over various brain regions, rapidly migrating to contralateral regions. Previous medications included 15 different AEDs, including magnesium bromide. RUF was added to zonisamide to a maximal dose of 50 mg/day (5 mg/kg/day). Parents described seizure worsening together with loss of appetite and treatment with RUF was stopped during the second week of therapy.

Patient 5 was a 36-month-old boy with multiple seizures per day from the age of 1.5 months. EEGs showed electro-clinical seizures from multiple areas including the bilateral temporal and frontal areas. MRI was normal and did not reveal a focal lesion. The patient had failed multiple treatments including lamotrigine, clonazepam, potassium bromide and the ketogenic diet. RUF was used as monotherapy with a maximal dose of 600 mg/day (60 mg/kg/day). After one month, treatment with RUF was stopped because of increased seizure frequency.

Discussion

All patients presented in this case series had clinical and electrographic characteristics fulfilling clinical criteria for MMPEI, including continuous migrating polymorphous focal seizures combined with multifocal ictal patterns (Coppola, 2009). Two of the five patients (Patients 1 and 2) had a dramatic response to RUF with a > 50% reduction in seizure frequency and no side effects. In another case (Patient 3), RUF was discontinued because of vomiting, and in the other two cases (Patients 4 and 5), RUF did not result in seizure reduction.

RUF is a triazole derivative which presumably exerts antiepileptic activity by prolonging sodium channel inactivity, stabilizing neuronal cell membranes (Cheng-Hakimian et al., 2006). It has a good oral absorption, a short half-life of six to ten hours, and is excreted renally as an inactive metabolite (Cheng-Hakimian et al., 2006; Perucca et al., 2008). RUF has limited interactions with other drugs, although valproic acid may increase plasma rufinamide concentrations, and carbamazepine, vigabatrin, phenytoin and phenobarbital can decrease RUF plasma levels (Brodie et al., 2009; Wheless and Vazquez, 2010). Previous reports suggest that RUF can be a useful add-on treatment option for children with different types of refractory epilepsy, including multi-focal epilepsies but not MMPEI (Kluger et al., 2009; Vendrame et al., 2010; Coppola et al., 2011; Biton et al., 2010).

From the cases reported here it is difficult to identify specific clinical features which were affected or not by RUF. Overall, the five patients had similar age, age of MMPEI onset, severity of MMPEI, and electro-clinical characteristics. No particular AED, used in combination with RUF, was associated with a lack of efficacy or poor tolerability. Of note, for one of the two cases with no efficacy of RUF, RUF was used as monotherapy (Patient 5). Reported side effects were vomiting and loss of appetite (Patients 3 and 4), similar to those previously described (Kluger et al., 2009; Vendrame et al., 2010; Coppola et al., 2010; Coppola et al., 2010).

The present study included children between 25 and 41 months of age. To date, there is limited data on the use of RUF in infants and small children, and only a few studies have included children less than four years of age (Vendrame et al., 2010; Kluger et al., 2010).In the present case series, the highest dose of RUF with efficacy and tolerability was 800 mg/day. Higher doses of 1,000 mg/day have also been safely used in children (Coppola et al., 2010). In adolescents and adults, adjunctive RUF at a dose of 3,200 mg/day was shown to be effective and safe in controlling partial-onset seizures (Biton et al., 2010).

Our results demonstrate good efficacy and tolerability of RUF in two of five cases with MMPEI. Although limited, these observations provide some hope for a novel therapeutic option for MMPEI and future studies are required to elucidate the validity of this new drug as therapy for this otherwise devastating syndrome.

Disclosure.

This study was funded in part (for S.V.K. and T.L.) by an Investigator Initiated Grant from Eisai Pharma, Inc.

Legends for video sequence Videoclip illustrating child with multiple tonic seizures in bilateral extremities.