5th Congress Autism-Europe
Articulos / Proceeding
Autism-Spain

MAGNESIUM VALPROATE THERAPY IN AUTISM WITH EPILEPSY OR EEG ABNORMALITIES.

Child Neuropsichiatry Service- U.S.L. 3 Catania, Italy.

Introduction

The association rate between autism and epilepsy is reported by many authors as 35 - 45 % (Gillberg,1987; Olsson, 1988), while it raises to about 60 % for EEG abnormalities only (Demyer,1973). Many studies suggest that some of the common antiepileptic drugs, like phenytoin, phenobarbitone and benzodiazepines, may be detrimental to the behavioural status of the child with autism and epilepsy (Gillberg,1991).

In many cases there are no clear clinical signs of epilepsy but an EEG with epileptogenic discharges. Carbamazepine and valproic acid are considered drugs of first choice for autistic children with epilepsy (Gualtieri,1987) for supposed psychotropic properties. In recent years, an alternative has been found to the well-known drug combination of valproic acid with sodium salt, i.e. a new drug in which magnesium replaces sodium (magnesium valproate). The encouraging results of vitamin B6-magnesium therapy have been reported (Lelord, 1981) on autistic children without epilepsy; a reduction in attention deficit-hyperactivity has been reported (Dell'Anna,1988) in epileptic children with associated behavioural disturbance treated with magnesium valproate.

In the present study, the safety and behavioural effects of magnesium valproate in autistic children with epilepsy or specific EEG abnormalities has been explored under clinical and laboratory monitoring.

Method

Nine autistic children, aged 3 to 12 years (mean, 7.02), were enrolled in this study. Five of them (first group) were without seizures but with EEG abnormalities like spikes, diffuse or focal, paroxysmal spike and wave activity, sharp-waves; we have not considered abnormal slowing alone. Four of them (second group) had a diagnosis of epilepsy associated and they were in treatment with phenobarbital in three cases and with sodium valproate in one case. All children (all males) met the DSM-III-R diagnostic criteria of infantile autism. one child from the first group had a meningoencephalitis at the age of six months while another one had an association with Hypomelanosis of Ito; in the second group one child had a diagnosis of West syndrome, one had the association with Tuberous sclerosis, one revealed a trisomy with translocation between chromosome 11 and 22. The kind of seizures are summarized in the table. Their intellectual functionnig ranged from moderate to profound mental retardation.

This was an open study. Four of the five children in the first group (without epilepsy) had been drug-free for 4 weeks before the 2 weeks baseline period; one child had been in treatment (by the paediatrist) with very low dose of phenobarbital for about ten years as a prophilaxis after the meningoencephalitis infection and some febrile convulsions: this treatment has been gradually replaced by magnesium valproate.

In the second group , with similar modality, in three children the phenobarbital has been replaced gradually while in the child (with previous West syndrome) treated with sodium valproate, the magnesium valproate has been rapidly introduced. Magnesium valproate was administered to the dose of 15 mg/kg/day, gradually reached in a two weeks' period; it was given twice a day (morning and evening), in the form of syrup. In order to control seizures in the second group, this dose might be elevated according to clinical exigences.

Baseline behavioural ratings were conducted prior to each magnesium valproate dosing, while post dosing ratings were taken at 8 weeks after the first dose. Each child was rated in a playroom during semistructured play observations by one child psychiatrist on Childhood Autism Rating Scale (CARS) (Schopler,1988); during the baseline period and the eighth week the parents rated the Behavioural Summarized Evaluation (BSE) (Barthelemy,1990).

EEG and some labora tory assessments, among which liver enzymes and plasmatic level of VPA (valproic acid), were carried out before magnesium valproate treatment and 8 weeks after.

Results

In all nine cases we have recorded a reduction in total scores, for both CARS and BSE. As shown in table, paired t-test for CARS comparing baseline evaluation with post-dosing ratings indicate significant improvement (D= 0.006); the only item showing more frequently (77.7%) a reduction is the one indicating "level of activity", in other items there is a diffusion of results.

Paired t-test for BSE indicate very significant improvement (p< 0.0005), the items more frequently in reduction are those regarding "attention deficit" and "excitement" (100%) and "intolerance to changes" (66.6%); interesting the reduction in "inadequate look" (44.4%).

At the EEG in all the children of the first group there was a sensible reduction of abnormalities and in two cases the disappearance of specific abnormalities; in the second grbup there was a reduction in two cases while no changes appeared in the other two (West syndrome and Tuberous sclerosis). The laboratory investigation didn't show any alteration.

The plasmatic level of VPA ranged from 35 to 95 (main 55.2) in the first group in which only in one case it has been necessary to raise the initial dose to control very high hyperactivity; in the second group the VPA level ranged from 42 to 91 (main 68.7). In the antepileptic action the magnesium valproate has showed the same efficacy as the other drugs previously used.

Discussion

In our daily clinical experience we still frequently meet autistic patients who are primarily treated for their associated epilepsy. This arouses strong doubts on the possible interference of antiepileptics on the rehabilitation programme. Consequently, it's of great importance, in our opinion, to well define the first choice antiepilectic drug specifically for autism symptomatology rather than only for type of epilepsy. In this sense valproic acid is also a recognized first choice drug for many epileptic syndroms. The presence of EEG abnormalities may be expression of a global brain dysfunction whose pharmacological reduction may favour a better functional adjustment by means of the global rehabilitation treatment. In particular, in our study we observed a positive action of magnesium valproate in reducing attention deficit and hyperactivity also in autistic children with only EEG abnormalities. All the children in this study were following a complete and integrated educative therapeutic programme, so we don't know which of the two, drug or educative stimulation, has more effect on the clinical global amelioration; in any case we recorded an acceleration in progress after the magnesium valproate introduction. In conclusion, we think that these findings require replication in a larger sample of patients possibly under doubleblind and placebo conditions but also comparing magnesium valproate versus other antiepileptic drugs with possible positive behavioural action (carbamazepine for instance).

References

Barthelemy C., Adrien J.L., Tanguay P., Garreau B., Fermian J., Roux S., Sauvage D., Lelord G. (1990). The Behavoural Summarized Evaluation: validity and reliability of a scale for the assessment of the autistic behaviors. Journal of Autism and Developmental Disorders,20, 189-201.

Dell'Anna M.E., Torrioli M.G., Calzolari S., Bagiella E.(1988). Child epilepsy and behavioral disorders: treatment with magnesium valproate. Rivista di Neuroscienze Pediatriche, 4, 165-172.

Gillberg C., Steffenburg S. (1987). Outcome and prognostic factors in infantile autism and similar conditions: a population -based study of 46 cases followed trough puberty. Journal of Autism and Developmental Disorders, 17, 273-287.

Gillberg C. (1991). The treatment of epilepsy in autism. Journal of Autism and Developmental Disorders, 21, 61-77.

Gualtieri T., Evans R.W., Patterson D.R. (1987). The medical treatment of autistic people. Problems and side effects. In: Schopler E. Mesibow G. Neurobiological Issues in Autism. New York: Plenum, 374-388.

Lelord G., Muh J.P., Barthelemy C., Martineau J., Garreau B. (1981) Effects of pyridoxine and magnesium on autistic symptoms; initial observations. Journal of Autism and Developmental Disorders,ll, 219-230.

Schopler E., Reichler R.J., Rochen Retiner B. (1988). The Childhood Autism Rating Scale. Los Angeles, Western Psychological Services.