Olivier Dulac

Antiepileptic drugs as a cause of worsening seizures

Summary: Purpose: Although the paradoxical ability of anti‐epileptic drugs (AEDs) to increase seizure activity has been recognized for decades, the underlying mechanisms are poorly understood and few systematic studies have addressed this problem. This article is intended to provide a critical review of available literature on this topic.

Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial

BACKGROUND Stiripentol is an inhibitor of cytochrome P450 that showed antiepileptic efficacy in severe myoclonic epilepsy in infancy (SMEI) in association with clobazam and valproate in an open study. To confirm these results, 41 children with SMEI were included in a randomised, placebo-controlled, add-on trial. METHODS After a baseline period of 1 month, placebo (n=20) or stiripentol (n=21) was added to valproate and clobazam during a double-blind period of 2 months. Patients then received stiripentol in an open fashion. Responders were defined as having more than 50% reduction in the frequency of clonic (or tonic-clonic) seizures during the second month of the double-blind period compared with baseline. FINDINGS 15 (71%) patients were responders on stiripentol (including nine free of clonic or tonic-clonic seizures), whereas there was only one (5%) on placebo (none were seizure free; stiripentol 95% CI 52.1-90.7 vs placebo 0-14.6). The 95% CI of the difference was 42.2-85.7. Percentage of change from baseline was higher on stiripentol (-69%) than on placebo (+7%), p<0.0001. 21 patients on stiripentol had moderate side-effects (drowsiness, loss of appetite) compared with eight on placebo, but side-effects disappeared when the dose of comedication was decreased in 12 of the 21 cases. INTERPRETATION This controlled trial shows the antiepileptic efficacy, of add-on stiripentol in children with SMEI. The results also provide good reason to focus studies on a specific epilepsy syndrome-a small sample of patients is sufficient to show the efficacy that might have been missed in a heterogeneous population.

Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis

Vigabatrin has been shown to be efficient in infants with infantile spasms and tuberous sclerosis, in open studies. In order to compare vigabatrin to oral steroids, a prospective randomized multicenter study was implemented using both drugs as monotherapy in newly diagnosed patients with infantile spasms and tuberous sclerosis. Eleven infants received vigabatrin (150 mg/kg per day) and 11 hydrocortisone (15 mg/kg per day) for 1 month. Spasm free patients continued vigabatrin or progressively stopped hydrocortisone in 1 month, non-responders were crossed to the other drug for a new 2 month-period. All vigabatrin patients (11/11) were spasm-free versus 5/11 hydrocortisone infants (P < 0.01). Seven patients were crossed to vigabatrin (six for inefficacy, one for adverse events) and became also totally controlled. Mean time to disappearance of infantile spasms was 3.5 days on vigabatrin versus 13 days on hydrocortisone (P < 0.01). Five patients exhibited side effects on vigabatrin but nine on hydrocortisone (P = 0.006). Vigabatrin should therefore be considered as the first choice treatment for infantile spasms due to tuberous sclerosis.

De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy.

Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. We performed exome sequencing in three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional individuals with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated affected individuals. Functional studies showed that the mutations led to constitutive activation of the channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C. In addition to regulating ion flux, KCNT1 has a non-conducting function, as its C terminus interacts with cytoplasmic proteins involved in developmental signaling pathways. These results provide a focus for future diagnostic approaches and research for this devastating condition.

Therapeutic Trial of Vigabatrin in Refractory Infantile Spasms

Infantile spasms usually start during the first year of life and constitute one of the most difficult types of epilepsy to treat. They carry a very poor prognosis for both epilepsy and mental development. Seventy children, including 47 infants, with intractable infantile spasms were entered into an open study with vigabatrin as add-on therapy to the usual anticonvulsant treatment. All were resistant to previous treatments, including corticosteroids (43 patients), carbamazepine, benzodiazepines, and sodium valproate. Two children withdrew from the study because of intolerance to vigabatrin (hypotonia or hypertonia) before evaluation of efficacy could be made. Of the remaining 68 children, 29 (43%) showed complete suppression of spasms. Forty-six children had a greater than 50% reduction in spasms. The best response was observed in those with tuberous sclerosis (12/14 compared with 12/18 with symptomatic infantile spasms of other origin and 22/36 with cryptogenic infantile spasms). Following the initial response to treatment of these patients (n = 68), a long-term response was confirmed in 75% of children with symptomatic infantile spasms and 36% of children with cryptogenic infantile spasms. In eight children, all other anticonvulsant medication could be definitively withdrawn. Tolerability appeared excellent, with 52 of 70 patients reporting no side effects. Somnolence, hypotonia, weight gain, excitation, and insomnia were the most common problems at the beginning of the study and were usually transient. Given the poor prognosis of this type of childhood epilepsy, vigabatrin appears to be a very interesting advance in the management of drug-resistant infantile spasms. (J Child Neurol 1991;6(Suppl):2S52-2S59).

Lamotrigine in Treatment of 120 Children with Epilepsy

Summary: One hundred twenty children aged 10 months to 16 years 9 months were included in three studies with lamotrigine (LTG): a single‐blind study (n = 60), a pharmacokinetic study (n = 23), and a compassionate group (n = 37). At 3 months, 11 patients had become seizure‐free and 34 had >50% decrease in seizure frequency. The best results involved absence epilepsy, Lennox‐Gastaut syndrome (LGS), and other symptomatic generalized epilepsy. Forty‐two patients were followed > 1 year, 22 for a mean of 2.2 years, and there was no significant increase in seizure frequency as compared with 3‐month follow‐up. Fourteen patients became seizure‐free for >6 months; all except 1 had generalized epilepsy. For 12 patients, treatment could be reduced to monotherapy, but for those with valproate (VPA) comedication LTG dosage had to be increased; 25% of patients with VPA monotherapy exhibited skin rash, appearing 3–18 days after starting LTG. For 4 patients, LTG could be reintroduced after VPA was withdrawn. Ten patients had ataxia and/or drowsiness and 2 had vomiting. For all other patients, tolerance was excellent.

Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients

Vigabatrin (VGB) has demonstrated high efficacy in infantile spasms (IS) due to tuberous sclerosis. Our first objective was to evaluate the cognitive long term effect outcome of children whose refractory spasms definitely disappeared when VGB was given as an add on drug. Our second objective was to determine the response of generalized epilepsy (infantile spasms) compared to partial epilepsy on cognitive impairment. A non selected series of 13 children underwent psychometric and behavioural evaluation before VGB initiation at a mean of 3 years on VGB treatment. Eight of them could perform detailed neuropsychological tests at follow-up. Seven had infantile spasms (Group I), they all were spasm free before 2 years of age and five remained with rare partial seizures (mean age, 5.5 years). Six others had partial epilepsy without spasms (Group II) and five remained with rare seizures (mean age, 7.5 years). Patients of Group I experienced dramatic changes. Developmental quotient (DQ) significantly rose in six out of seven by ten to more than 45 points (P = 0.03) and autistic behaviour disappeared in five out of the six who presented with. The four tested children had normal verbal level after 5 years and could integrate at school but they remained with marked visuospatial disabilities. By contrast, patients of Group II remained with an unchanged DQ of about 60 so that both groups had similar DQ levels on follow-up. The cessation of spasms with VGB is therefore associated with significant improvement of cognition and behaviour in children with tuberous sclerosis. Controlling secondary generalization induced by infantile spasms seems to be a key factor for mental development.

Verbal and visual memory impairment in childrem with epilepsy

Verbal and visual memory performances were evaluated in 60 epileptic children and 60 normal control subjects with Signorets Memory Battery scale. Eighteen patients had idiopathic generalized epilepsy and 42 had partial epilepsy, mostly of the temporal (n = 28) and frontal (n = 10) lobes. Memory scores were statistically lower in epileptics than in controls and significant differences were found within each group: (1) children with idiopathic generalized epilepsy had a slight depression of visual memory; (2) memory disorder was more severe in partial epilepsy; and (3) children with left and right temporal lobe epilepsy had marked memory deficits related to hemispheric specialization.

Migrating Partial Seizures in Infancy: A Malignant Disorder with Developmental Arrest

Summary: Fourteen infants of both sexes had a previously unreported epileptic condition characterized by nearly continuous multifocal seizures. The first seizures occurred at a mean age of 3 months, without antecedent risk factors. At 1 to 10 months, the seizures became very frequent. They were partial with variable clinical expression, and the EEG showed that the discharges randomly involved multiple independent sites, moving from one cortical area to another in consecutive seizures. Although their topography varied, the EEG ictal pattern of each seizure was very similar. It consisted of rhythmic alpha or theta activity which spread to involve an increasing area of the cortical surface. Patients regressed developmentally and became quadriplegic with severe axial hypotonia. Three patients died at age 7 months and at age 7 and 8 years, respectively. Seizures were controlled in only 2 patients, and only 3 children resumed psychomotor development. Extensive investigation failed to determine an etiology, and there was no familial recurrence. Neuropathological examination of the brain in two cases showed only severe hippocampal neuronal loss and accompanying gliosis.

Deficits in executive functions and motor coordination in children with frontal lobe epilepsy

Frontal lobe dysfunction in adults has been associated with impairments of planning abilities, working memory, impulse control, attention and certain aspects of motor coordination. However, very few studies have attempted to assess these functions in children suffering from frontal lobe epilepsy. The aim of the present study was to determine whether some or all of the components of the frontal lobe syndrome are present in children with this disorder. For this purpose, a neuropsychological test battery was administered to 32 unresected epileptic children, aged 8-16 years: 16 with frontal lobe epilepsy (FLE), eight with temporal lobe epilepsy (TLE) and eight with generalized epilepsy whose principal manifestations were typical absences (GEA). The performances of the three epileptic groups were further compared to normative data derived from 200 French-speaking, healthy children aged 7-16 years, except for standardized tests for which the norms provided in the manual were used. The three epilepsy groups did not differ with respect to conceptual shift and recency memory. However, the FLE children showed deficits in planning and impulse control. Furthermore, they had significantly more coordination problems and exhibited greater rigidity than the other epilepsy groups on the motor tests. These problems were more marked in younger FLE children (8-12 years). The latter were also more impaired on verbal fluency measures. No differences were observed with respect to gender, localization of the epileptic abnormality (unilateral versus bilateral) or medication (monotherapy versus polytherapy). The findings reveal similarities between the neuropsychological profiles of FLE children and adults with frontal lobe lesions.