First European long-term experience with the orphan drug rufinamide in childhood-onset refractory epilepsy.

OBJECTIVE: Recently, we published the first postmarketing European experience with rufinamide (RUF) in a retrospective 12-week observational study. This follow-up report summarizes the long-term effectiveness and tolerability of RUF after 18 months for the same patient sample. METHODS: In total, 52 of 60 initially included patients from eight centers in Germany and Austria (45 children and 15 adults aged 1-50 years) with various severe and inadequately controlled epilepsy syndromes continued treatment with RUF after the initial 3-month observation period (mean final dose: 38.2+/-17.3mg/kg/day). Efficacy was assessed by seizure frequency evaluated by comparison with baseline frequency. Tolerability was evaluated by analysis of parental report of adverse events and laboratory tests. Responders were defined as patients who achieved a 50% or greater decrease in countable seizures within 18 months of initiating RUF therapy. RESULTS: Mean overall duration of RUF treatment was 14.5 months (range: 3-18 months). Retention rate, defined as the percentage of patients still taking RUF after 18 months, was 41.7% (n=25/60). The overall response rate after 18 months was 26.7% (16/60 patients). The highest response rates were found in the subgroup of patients with Lennox-Gastaut syndrome (LGS, 35.5%) and in patients with other generalized epilepsy syndromes. Complete seizure control was maintained in one patient (1.6%). A total of 73 adverse events were reported in 37 of 60 patients. The most frequently occurring adverse events were fatigue (18.3%), vomiting (15.0%), and loss of appetite (10.0%). Only 4 new adverse events were reported after week 12. No serious adverse events were observed. CONCLUSIONS: The present data suggest that RUF is efficacious and well tolerated in the long-term treatment of children and adults with various epilepsy syndromes and difficult-to-control seizures.

Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy.

Heterozygous mutations in the CLCN2 gene encoding the voltage-gated chloride channel CLC2 have been identified in patients with idiopathic generalized epilepsy (IGE). Yet the involvement of CLCN2 in epilepsy remains controversial. To investigate the involvement of CLCN2 in another independent sample, we screened 52 unrelated patients from IGE families and 23 patients with Doose syndrome for mutations in CLCN2. No mutations were found in patients with Doose syndrome. In three unrelated IGE families, we identified two novel missense mutations, p.Arg235Gln and p.Arg577Gln, which were absent in large ethnically-matched control populations, and one novel p.Arg644Cys variant, which was also found in five Indian controls. Functional characterization of mutant channels using heterologous expression in mammalian cells and whole-cell patch-clamp recordings revealed faster deactivation kinetics as the major phenotype of both missense mutations. This finding predicts a loss of function that may contribute to intracellular chloride accumulation or neuronal hyperexcitability. However, the incomplete segregation of the mutations among affected members and the transmission by unaffected parents suggests that these CLCN2 mutations alone are not sufficient to induce epilepsy. They may instead represent susceptibility factors among other so far undetected genetic alterations in the respective families.

Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology.

Lennox-Gastaut syndrome is one of the most severe epileptic encephalopathies of childhood onset. The cause of this syndrome can be symptomatic (ie, secondary to an underlying brain disorder) or cryptogenic (ie, has no known cause). Although Lennox-Gastaut syndrome is commonly characterised by a triad of signs, which include multiple seizure types, slow spike-wave complexes on electroencephalographic (EEG) recordings, and impairment of cognitive function, there is debate with regard to the precise limits, cause, and diagnosis of the syndrome. Tonic seizures, which are thought to be a characteristic sign of Lennox-Gastaut syndrome, are not present at onset and the EEG features are not pathognomonic of the disorder. There are few effective treatment options for the multiple seizures and comorbidities, and the long-term outlook is poor for most patients. Probably as a result of the complexity of the disorder, only a few randomised trials have studied Lennox-Gastaut syndrome, and thus many of the drugs that are more commonly used have little or no supporting evidence base from controlled trials. In this Review, we discuss the main issues with regard to the diagnosis and treatment options available. We also suggest key considerations for future trials and highlight the importance of a comprehensive approach to the assessment and management of this syndrome.

Effectiveness and tolerability of rufinamide in children and adults with refractory epilepsy: first European experience.

OBJECTIVE: The aim of the study was to explore the effectiveness and tolerability of rufinamide in a heterogeneous group of patients with refractory epilepsies in Europe, immediately after the drug became available as an orphan drug for the adjunctive treatment of Lennox-Gastaut syndrome (LGS). METHODS: This observational study was conducted as a collection of retrospective data from multiple centers in Germany and Austria. Clinical course in patients treated with rufinamide was documented. Initial dosage and titration schedule of rufinamide were at the discretion of the treating physician according to medical need. The observation period was 12 weeks. Effectiveness was evaluated by comparing the frequency of seizures with limitations to the countability between baseline and the last 4-week period of observation. RESULTS: The study population consisted of 45 children and 15 adults (mean age: 14.5+/-11.6 years, range: 1-50) with various severe and inadequately controlled epilepsy syndromes, that is, LGS (n=31), idiopathic generalized epilepsy syndromes (n=5), cryptogenic unclassified generalized epilepsy (n=7), and partial epilepsy (n=17). The response rate (50% reduction in countable seizures) was 46.7% (28 of 60 patients) in total; 25.0% experienced a 75% reduction in seizure frequency and 21.7% experienced a 50-75% reduction. Complete seizure control was achieved by 8.3%. The highest response rate was observed in patients with LGS (17/31, 54.8%), and the lowest in patients with partial epilepsy (4/17, 23.5%). Response rate in patients with unclassified generalized epilepsy was 42.8% (3/7 patients). A total of 67 adverse events were reported by 35 of 60 patients. The most frequently occurring adverse events were fatigue (18.3%), vomiting (13.3%), and loss of appetite (10.0%). No serious adverse events were observed. CONCLUSIONS: These preliminary data suggest that rufinamide may be effective and well tolerated in the treatment of children and adults with various epilepsy syndromes and difficult-to-control seizures. The results of our study suggest that the efficacy of rufinamide in patients with generalized epilepsy might be comparable to that in patients with LGS, whereas rufinamide was less effective in patients with partial epilepsy.

Effects of Levetiracetam and Sulthiame on EEG in benign epilepsy with centrotemporal spikes: A randomized controlled trial.

PURPOSE: BECTS (benign childhood epilepsy with centrotemporal spikes) is associated with characteristic EEG findings. This study examines the influence of anti-convulsive treatment on the EEG. METHODS: In a randomized controlled trial including 43 children with BECTS, EEGs were performed prior to treatment with either Sulthiame or Levetiracetam as well as three times under treatment. Using the spike-wave-index, the degree of EEG pathology was quantified. The EEG before and after initiation of treatment was analyzed. Both treatment arms were compared and the EEG of the children that were to develop recurrent seizures was compared with those that were successfully treated. RESULTS: Regardless of the treatment agent, the spike-wave-index was reduced significantly under treatment. There were no differences between the two treatment groups. In an additional analysis, the EEG characteristics of the children with recurrent seizures differed statistically significant from those that did not have any further seizures. CONCLUSION: Both Sulthiame and Levetiracetam influence the EEG of children with BECTS. Persistent EEG pathologies are associated with treatment failures.

Pharmacology, efficacy, and tolerability of potassium bromide in childhood epilepsy.

This study investigated the efficacy and tolerability of potassium bromide in 113 patients (aged, 1-20 years) with severe epilepsy and generalized tonic-clonic seizures. Potassium bromide was started at 45 mg/kg and raised to 70 mg/kg (median). Steady-state blood level was reached after a median of 28 days (range, 5-95 days). The number of patients who had suffered generalized tonic-clonic seizures during the last month dropped from 82 to 41, and the median frequency, dropped from 4.5 to 0 per month. Of the patients with generalized tonic-clonic seizures during baseline, 49% showed none in the last 4 weeks of the study, and another 31% showed a reduction by more than 50%. Potassium bromide should have a place as a drug of tertiary choice in the treatment of children with epilepsy. Experience with the drug and close clinical and pharmacologic monitoring are necessary to achieve the greatest possible benefit and avoid side effects.

Atypical case of Aicardi-Goutières syndrome with late-onset myoclonic status.

Aicardi-Goutières syndrome (AGS) is a rare, progressive, autosomal recessive encephalopathy characterised by basal ganglia calcifications, chronic CSF lymphocytosis, and negative serological investigations for the common prenatal infections. The clinical profile is characterised by acquired microcephaly, mild to severe cognitive delay and dystonia. Epilepsy is usually not prominent. We report on a 19-year-old patient with an atypical clinical course, characterized by a relatively benign presentation at onset. Epilepsy with complex-focal seizures, possibly with a visual aura and sometimes with secondary generalization, started at the age of nine years. Clinical deterioration occurred later, and at the age of 17 years he experienced severe, generalized, myoclonic attacks lasting hours, which were partly controlled by the administration of piracetam.[Published with video sequences].