Congenital variant Rett syndrome in a girl with terminal deletion of chromosome 3p.

A girl fulfilling four/five of six inclusion criteria and eight/nine of 11 supportive criteria for atypical Rett syndrome had a cytogenetic deletion of chromosome 3p, del(3)(pter-->3p25.1 approximately 25.2). The deletion was situated on the maternally derived chromosome and by molecular analysis the deletion breakpoint was shown to be between DNA markers D3S3589 and D3S1263.

Antiepileptic drug-related cognitive complaints in seizure-free children with epilepsy before and after drug discontinuation.

The cognitive complaints reported by children and their parents, as subjectively associated with antiepileptic drug (AED) treatment, were evaluated in seizure-free children before and after drug discontinuation. The aim of the design was to isolate the cognitive side effects of AEDs from other factors, such as the effect of seizures. Our inventory explored the following areas: "alertness," "concentration," "activation/ tiredness," "memory," "drowsiness," "depression," "aggressiveness," and "hyperactivity," using a 5-point Likert scaling procedure. One hundred two eligible patients were selected, each matched with a healthy control and assessed when still on antiepileptic medication. All children were seizure free for at least 1 year. The medication was then discontinued gradually over a 3-month period. Four months after the children were completely medication free, a second assessment was carried out, but only in the 83 children who remained seizure free and in their matched controls. The results of the reports made by the children themselves did not show differences with the matched controls, and only showed improvement after drug discontinuation for complaints about "tiredness." Parents of the children with epilepsy reported significant improvement in all areas related to "alertness and activation" after discontinuation of the drugs. The finding that only a limited number of children have cognitive complaints, both when still on AEDs and after discontinuation, may be in line with the reports that the major factor contributing to quality of life is whether patients are seizure free or still have seizures. All patients in this study were seizure free for a period >1 year, which may have caused the favorable pattern of response in our patient group.

Lamotrigine in Rett syndrome: treatment experience from a pilot study.

This open pilot study was performed to evaluate the effect of Lamotrigine (LTG) in girls with Rett syndrome (RS) regarding seizure frequency, effect on gross motor dyspraxia and safety. Twelve girls with either the classical form of RS or the milder form fruste variants were included. The effect on epilepsy was evaluated as seizure frequency, motor performance (video comparison) and safety at clinical check up. The dosage of LTG was individualized and related to concomitant anti-epileptic drugs. Two of three girls with epilepsy responded relatively well to treatment, and for one of them even bad tantrums disappeared. LTG was useful in another four girls who became happier, more alert, more able to concentrate, and improved in contacting. Only mild adverse reactions as rash and tremor were seen. It is concluded that LTG could be worth trying as an adjunct in girls with RS, being aware of possible adverse reactions and no effect at all.

Replacing carbamazepine slow-release tablets with carbamazepine suppositories: a pharmacokinetic and clinical study in children with epilepsy.

A suppository for rectal administration of carbamazepine has been developed for situations in which it is unsuitable to use the oral route of administration. In an open, controlled, within-patient study, the pharmacokinetics, clinical efficacy, and tolerability of carbamazepine slow-release tablets were compared with those of carbamazepine suppositories in children with epilepsy. The pharmacokinetic part of the study comprised 22 children, and an additional nine children were included in the clinical part of the study. Treatment with slow-release tablets was replaced for 7 days with carbamazepine suppositories in bioequivalent dosage. Clinical factors such as the rate of seizures and the local tolerability were studied, and an overall assessment of efficacy was made. In the pharmacokinetic part, 24-hour plasma concentration curves for carbamazepine and carbamazepine-10,11-epoxide were recorded. The plasma concentration profiles (minimum, maximum, and mean concentrations, fluctuation index, and area under the curve) for carbamazepine and the other metabolites did not show any significant differences between oral and rectal administration when the suppository dose was increased by 25% compared to the tablets. No increase in seizure frequency was detected, and the overall assessment was very good to good in 25 of the 29 epileptic children. Increased flatulence during treatment with suppositories was noted in two children, one had anal irritation, and one had nausea/vomiting. Treatment with carbamazepine slow-release tablets in children with epilepsy can be replaced by carbamazepine suppositories in 25% higher dosage, with good clinical effect and appropriate pharmacokinetic values, when it is unsuitable to use the common oral route of administration.

Withdrawal of antiepileptic medication in children. Correlation of cognitive function and plasma concentration--the multicentre 'Holmfrid' study.

Eighty-three patients with epilepsy and 83 matched controls completed 12 computerized cognitive tests while on antiepileptic drugs and six months later when they had been medication-free for three to four months. All patients had been seizure-free for more than one year and were on monotherapy with carbamazepine (CBZ, n = 56), valproate (VPA, n = 17), or phenytoin (PHT, n = 10). The tests and plasma concentration collection were done at noon. The mean peak plasma concentrations in the CBZ patients were as follows: 31% below 30 mumol/l, 48% between 30 and 42 mumol/l and 21% above 42 mumol/l. No difference in performance could be detected between the groups. One significant correlation between plasma concentration and test results was found. The mean VPA concentration was 625 mumol/l (S.D. 189). A tendency towards a weak negative correlation between test results and plasma concentration was present. The PHT patients' therapeutic range had a mean concentration of 32.0 mumol/l (S.D. 18.5). One significant correlation between a memory test and plasma concentration could be detected. Overall, the patients in the different antiepileptic groups performed less good than the control group and in a few cases the differences were statistically significant when compared either before or after withdrawal. A comparison of the changes after withdrawal showed improvement in the majority of tests, but these changes were also present in the matched control group.

Lamotrigine in Rett syndrome.

An elevated CSF glutamate level has recently been reported in Rett syndrome. Because the anticonvulsant effect of Lamotrigine is probably due to inhibition of glutamate release, this drug was given as an add-on drug to 4 girls with Rett syndrome. All patients responded with a seizure reduction of 50% or more and an improved well-being. A controlled study at the early stages of the syndrome could be interesting.

Withdrawal of antiepileptic medication in children--effects on cognitive function: The Multicenter Holmfrid Study.

We present 100 children diagnosed with epilepsy who were seizure-free for more than 1 year and still on monotherapy of antiepileptic drugs (AEDs). We matched each child with a healthy classmate and performed neuropsychological testing and EEG before and after complete withdrawal of the AEDs. The withdrawal phase lasted 3 months, but the dose decrease was individualized for each patient. Three to 4 months after complete withdrawal of the drug all patients were reassessed. Patients with seizure relapse are excluded from the study. Seventeen patients are regarded as dropout, 11 because of seizure relapse and six because of protocol violation. The remaining 83 patients were treated with carbamazepine (n = 56), valproic acid (n = 17), or phenytoin (n = 10). Serum concentrations of the AEDs were measured using peak plasma levels that were taken immediately before or after psychological testing. We used neuropsychological tests to assess psychomotor function and "central" cognitive processing such as information processing or memory function. We found significant improvement attributable to drug withdrawal on only one of the cognitive tests, namely, psychomotor speed, suggesting that the impact of AED treatment on higher-order cognitive function is rather limited. In addition, we found group differences between the epilepsy group and the control group at baseline that persisted after drug withdrawal. Subsequent analysis showed some factors that may have contributed to these group differences. First, patients with a former diagnosis of absence seizures show lower scores both at baseline and after drug withdrawal. We may assume that the seizure propensity has not disappeared completely in these patients. Some evidence is found that phenytoin may have a different cognitive profile than carbamazepine, with more impairment on tests that measure motor and mental speed. Again, this impairment persists after drug withdrawal.

Diurnal variation of carbamazepine and carbamazepine-10,11-epoxide in plasma and saliva in children with epilepsy: a comparison between conventional and slow-release formulations.

In order to overcome the problems of interdosage fluctuations of body fluid concentrations of carbamazepine, a slow-release formulation has been developed. In an open, controlled, within-patient study, the diurnal plasma concentrations of carbamazepine and its 10,11-epoxide were measured in 25 epileptic children first treated with conventional carbamazepine tablets (Tegretol) and then with the Tegretol slow-release preparation. The diurnal plasma concentration curves during treatment with the slow-release formulation showed significantly less variation over 24 hours than during treatment with the ordinary preparation, as measured by the fluctuation index. Mean concentration values also differed significantly, which is explained by a somewhat reduced bioavailability (22% less) of the slow-release formulation. There were no differences in efficacy and tolerability between the two formulations, but there was a clear-cut reduction of reported side effects, especially tiredness, on treatment with the slow-release formulation. For that reason, the slow-release formulation should be a major advantage in treating children with epilepsy, in order to avoid interference with cognitive functions. In 12 children, simultaneous measurements of the concentration of carbamazepine and its epoxide in saliva were made and compared with the plasma values. As expected, the concentration curves corresponded, indicating that saliva sampling is an appropriate alternative for monitoring the concentration of carbamazepine. All children remained on the slow-release preparation after the trial and were followed up for 12 months or more.

Discontinuation of antiepileptic drugs in children who have outgrown epilepsy: effects on cognitive function.

Cognitive function is frequently impaired in children with epilepsy, compared with age-matched controls. It can be hard to evaluate the significance of various contributory factors. The effects of antiepileptic drugs may be studied in children who have outgrown their epilepsy but are still being treated. A multicenter study to assess various aspects of cognitive function in children with different forms of epilepsy, both during and after treatment with antiepileptic drugs, is currently under way. Definitive results are not yet available; interim analysis of the findings suggests that short-term memory is decreased in all subgroups of children being treated for epilepsy, compared to controls.

Disialotransferrin developmental deficiency syndrome.

Seven mentally deficient children and adolescents (three pairs of siblings and one singleton) were studied. A peculiar external appearance, a characteristic neurohepatosubcutaneous tissue impairment syndrome and, as a biological marker, an abnormal sialic acid transferrin pattern were characteristic features. All seven seemed odd from birth and prone to acute cerebral dysfunction during catabolic states. Abnormal lower neurone, cerebellar, and retinal functions dominated from later childhood. The disialotransferrin pattern found in serum and cerebrospinal fluid is thought to be the biological marker of a newly discovered inborn error of glycoprotein metabolism with autosomal recessive inheritance.

Salla disease variants. Sialoylaciduric encephalopathy with increased sialidase activity in two non-Finnish children.

The case reports of two Swedish girls with initially pseudostationary clinical pictures, one simulating ataxic and the other dyskinetic cerebral palsy, are presented. It was eventually revealed that they had a slowly progressive encephalopathy with pronounced gross motor disability and signs of severe dyskinesia, but only mild intellectual delay. Electron microscopy of skin biopsies showed a picture identical to that in Salla disease. They had a moderately increased 5-10 fold urinary free sialic acid excretion, increased sialidase activity in lymphocytes but normal activity in cultured fibroblasts. These two Swedish cases represent variants of Salla disease, a group of conditions with probable genetic heterogeneity.