Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients
Introduction
Mental disability and behaviour troubles are major characteristics of tuberous sclerosis (Gomez, 1988, Shepherd and Stephenson, 1992, Gillberg et al., 1994). Most patients who develop severe mental retardation have suffered from early onset epilepsy, mainly consisting of infantile spasms (Riikonen and Simell, 1990, Jambaque et al., 1991). In addition to mental retardation, children with tuberous sclerosis have a high incidence of behaviour disorders, including autism and hyperactivity (Riikonen and Amnell, 1981, Bolton and Griffiths, 1997). In patients with infantile spasms whatever the etiology, there is a high incidence of mental retardation together with a wide range of behaviour troubles, including autistic features (Koo et al., 1993), and persisting seizures with secondary generalization contributes markedly to worsening mental outcome regardless of etiology.
In a previous study, we indicated that the variability of neuropsychological disorders observed in children with tuberous sclerosis could be correlated with the severity of epilepsy and the type of syndrome exhibited by the patient, the latter resulting from the topography of tubers seen on magnetic resonance imaging (Jambaque et al., 1991). Patients with one or two epileptogenic tubers usually exhibit partial epilepsy with the corresponding selective neuropsychological deficit but do not suffer from global deterioration (Cusmai et al., 1990). On the other hand, severe mental retardation and autistic behaviour frequently occurred as late sequelae in children having numerous tubers with both posterior and anterior location who had intractable seizures including protracted infantile spasms (Jambaque et al., 1993). We therefore hypothesized that a better control of epilepsy, particularely in patients with infantile spasms, could significantly improve mental and behavioural outcome.
Infantile spasms due to tuberous sclerosis have long been considered to be among the most intractable, but recent studies have demonstrated that a new antiepileptic drug, vigabatrin (VGB), is highly successful in controlling infantile spasms in patients with tuberous sclerosis since 80–100% of them become spasm free (Chiron et al., 1991, Chiron et al., 1997). Partial seizures also respond relatively well to VGB in tuberous sclerosis (Nabbout et al., 1997). Therefore, this condition provides the opportunity to determine whether controlling infantile spasms could contribute to the prevention of the development of cognitive deterioration and autistic behaviour, and to evaluate the responsability of generalized epilepsy (infantile spasms) compared to partial epilepsy on cognitive impairment.
The present study was dedicated to children with tuberous sclerosis and had two objectives. The first was to evaluate the behavioural and cognitive follow-up in patients whose spasms were controlled with VGB. The second was to compare them to another group of patients also treated with VGB and evaluated in the same way but having partial epilepsy.
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Selection criteria
All the children with tuberous sclerosis referred to our center who received VGB between 1987 and 1992 (before approval) and having undergone longitudinal neuropsychological evaluation for at least 2 years entered the study. Among the 29 patients with tuberous sclerosis treated with VGB in add-on for refractory epilepsy, 16 could not be assessed longitudinally from the neuropsychological point of view. Of the remaining 13 patients, seven presented with infantile spasms (Group I) and six with
Psychometric and behavioural evaluation
The global measure of mental development was based on the French Gesell adaptation (Brunet and Lezine, 1983), Terman Merrill (Cesselin, 1988) and Wechsler-scales (Wechsler, 1974, Wechsler, 1981), resulting in developmental quotient (DQ) or intelligence quotient (IQ) according to age and mental stage. This psychometric evaluation was performed at least twice in all patients, at VGB onset and at last visit on VGB (Table 2). All patients had assessment of DQ before VGB initiation except one (#13)
Group I
Before VGB onset, all seven children exhibited moderate to severe mental retardation and their social interaction was poor or completely lacking (Table 2). Five of them had clearly autistic behaviour, often combined with hyperactivity. After spasms had disappeared with VGB, DQ rose by at least ten points in six out of seven patients (P=0.03). In four of them, it rose by at least 20 points, including one by more than 30 and another by more than 40. Four patients were able to have IQ assessment
Discussion
Our findings show that infants with tuberous sclerosis whose infantile spasms come under control with VGB benefit from a clear long term cognitive and behaviour improvement, even when partial seizures persist. On the other hand, although tuberous sclerosis children treated with VGB for partial epilepsy benefit from ongoing cognitive acquisitions, they do not exhibit any significant improvement in psychometric tests. We hypothesize that complete cessation of the generalized epileptic phenomena
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