Oxcarbazepine-induced hyponatremia and the regulation of serum sodium after replacing carbamazepine with oxcarbazepine in children.

While severe hyponatremia is reported to be more frequent in adults treated with oxcarbazepine (OXC) than with carbamazepine (CBZ), there is not sufficient data about the incidence of hyponatremia in childhood during treatment with OXC. We evaluated changes in serum electrolyte balance in 75 children with epilepsy before and during treatment with OXC and after replacing carbamazepine (CBZ) therapy with OXC therapy. All patients had normal sodium serum levels at the onset of OXC. During treatment with OXC we found hyponatremia (Na +< 135 mmol/l) without clinical symptoms in 26.6 % of the children (n = 20), sodium levels below 125 mmol/l were observed in 2 children (2.6 %). Clinically relevant hyponatremia occurred in one girl only (1.3 %). In a subgroup of 27 children, in whom CBZ was directly replaced with OXC, hyponatremia without symptoms was found in one child under CBZ (3.7 %) and in six children under OXC (22.2 %). Dosage of OXC, serum levels of the active metabolite of OXC, antiepileptic comedication or patients' age and gender were of no predictive value for the development of hyponatremia. Electrolytes should be measured before establishing OXC and if clinically relevant side effects occur.

Multiple pterygium syndrome, bilateral periventricular nodular heterotopia and epileptic seizures--a syndrome?

We present the clinical, neurophysiological and radiographic findings in a boy with coexisting multiple pterygium syndrome, bilateral periventricular nodular heterotopia (BPNH), mental retardation and epileptic seizures. This constellation has not been previously reported. We discuss the possibility of a new BPNH syndrome associated with multiple pterygium syndrome in our patient.

Effective and safe but forgotten: methsuximide in intractable epilepsies in childhood.

The efficacy and safety of methsuximide (MSM) was evaluated in children with intractable epilepsies in a prospective uncontrolled study. MSM was added to the therapeutic regimen of 112 children with intractable epilepsy under inpatient conditions, all of whom were therapeutically refractory to various first-line antiepileptic drugs (AED) or combinations of other AED. Titration of MSM was performed following a uniform protocol. Administration of MSM resulted in a 50% or greater reduction in seizure frequency in 40 patients after a short-term observation period (mean 9.1 weeks). After a mean of 3.7 years, the rate of seizures and side effects were re-evaluated in 39 patients who were still receiving MSM as part of their antiepileptic regimen. Twenty two of these patients derived long-term benefit from MSM. In patients with good seizure control, fasting plasma levels of N-desmethylmethsuximide, the principal active metabolite of MSM, were 25.3-44.7 mg l(-1)(mean 36.0 mg l(-1)). Thus effective plasma levels of N-desmethylmethsuximide in children were found to be higher than previously described. Forty one of 112 patients (28.9%) developed side effects during MSM treatment. No serious or irreversible side effects were seen. Our study demonstrates the value of MSM as an 'add-on' drug in intractable epilepsies.

Carbamazepine-induced combined phonic and motor tic in a boy with Down's syndrome.

We report the occurrence of a tic in a boy with Down's syndrome. The movement disorder was induced by carbamazepine (CBZ) and resolved completely after discontinuation of CBZ. The development of tics seems to be a rare, idiosyncratic side effect of CBZ in children.

Seizure-inducing paradoxical reaction to antiepileptic drugs.

We report on an 18-month-old girl with a seizure frequency of five/day, receiving an antiepileptic polytherapy consisting of primidone, clonazepam and phenytoin. Following discontinuation of clonazepam and primidone, the patient has been seizure-free under monotherapy for 2 years and shows marked developmental progress. Possible mechanisms of this paradoxical effect of antiepileptic drugs and the implications for antiepileptic therapy are discussed.

Gabapentin in childhood epilepsy: a prospective evaluation of efficacy and safety.

PURPOSE: To evaluate the efficacy and safety of gabapentin (GBP) in partial epilepsy in children. METHODS: We performed a prospective open label add-on study in 52 children and adolescents (age 1.8-17.5 years, mean 11.1 years) with refractory partial seizures. Gabapentin was added to one other baseline drug and the efficacy was rated according to seizure type and frequency. RESULTS: The GBP dose ranged from 26 to 78 mg/kg per day (mean 52 mg/kg per day) and was well tolerated in most patients. The seizure frequency remained unchanged in 34 patients (65%). We saw a provocation of seizures in three children (6%). Initially 15 patients (29%) benefited from GBP: five (10%) with a seizure reduction of 50-74%, seven (13%) with a reduction of 75-99% and three (6%) became seizure free. All but three experienced a development of tolerance within the next weeks to months. CONCLUSIONS: Although gabapentin seems also to be safe in children, the efficacy in refractory partial seizures was disappointing.

[Recommendations for blood studies and clinical monitoring in early detection of valproate-associated liver failure. Results of a consensus conferences 9 May - 11 May 1997 in Berlin]. / Empfehlungen zu Blutuntersuchungen und klinischer Uberwachung zur Früherkennung des Valproat-assoziierten Leberversagens. Ergebnisse einer Konsensus-Konferenz vom 9.5.-11.5.1997 in Berlin.

Valproate is a frequently used antiepileptic drug. It is associated with rare but serious adverse effects like liver failure. The first symptom is impairment of the patient's well being. Isolated changes of standard laboratory liver parameters are not reliable early indicators. Thus, according to the knowledge of today, prophylactic blood screening cannot predict complications. On the contrary, clinical symptoms are the most relevant indicators of impending complications, eventually supported by laboratory findings. An abrupt withdrawal of valproate and administering carnitin in parallel can interrupt the otherwise fatal course of the complication and induce a subsequent recovery. At a Consensus Conference the current knowledge about early detection and therapy of the valproate-induced serious hepatotoxicity was discussed. The results regarding recommended laboratory screening, as well as diagnostic and therapeutic strategies are reported.

Hyponatremia induced by oxcarbazepine in children.

We report the case of a 12-year-old girl with severe clinically relevant hyponatremia (118 mmol/l) and hypochloremia (81 mmol/l) during treatment with oxcarbazepine (OCBZ). The adverse effects were rapidly reversible after discontinuation of OCBZ and did not occur when exposed to carbamazepine. We reviewed the charts of 48 patients who received OCBZ as in-patients in our epilepsy centre and found hyponatremia in nine and hypochloremia in four. The mean sodium level of all patients was 139 mmol/l (range 118-150 mmol/l). We did not see any correlation between sodium or chloride levels and dose of OCBZ or blood serum level of the active metabolite 10-OH-carbazepine. We emphasize that children are at risk of developing electrolyte disturbances during treatment with OCBZ and thus the level of at least sodium should be monitored in those patients.

Influence of ethosuximide on valproic acid serum concentrations.

In the therapy of absence epilepsies, a combination of ethosuximide (ESM) and valproic acid (VPA) is sometimes necessary for a successful seizure control. Previous studies of the interaction between ESM and VPA revealed contradictory results. We investigated the influence of ESM on VPA serum concentrations in children with epilepsy. In case of ineffectiveness of the drug, ESM was withdrawn (n = 9). Four children treated with VPA got ESM additionally because their seizure control was insufficient with VPA alone. Two children had bromide, and one clobazam as comedicament. Both of these antiepileptic drugs (AEDs) do not have any known interactions with ESM or VPA. Serum levels of VPA were higher in monotherapy than in combination with ESM (120.0 +/- 20.1 micrograms/ml; range, 88.9-153.4 micrograms/ml; vs. 87.0 +/- 13.1 micrograms/ml; range, 67.4-108.0 micrograms/ml). The difference was statistically significant (P < 0.01). After stopping ESM the serum concentrations of VPA rose about 36.7%; when combined with ESM they fell about 28.3%. Neither the age of the patients nor the serum concentrations of ESM influenced significantly the changes of VPA serum levels in either group. The mechanism of ESM to influence the serum levels of VPA remains unknown. ESM has no known enzyme inducing properties. The interaction of ESM and VPA ought to be considered in a combination therapy of these drugs.

Pharmacokinetics of sulthiame in epileptic patients.

Sulthiame is an antiepileptic drug that was introduced approximately 30 years ago for the treatment of epilepsy. Currently it is rarely used, but recent studies show its efficacy, especially in the treatment of focal epilepsies in children. Because there are hardly any pharmacokinetic studies of sulthiame in humans, we studied the dose-level relationship, the elimination half-life, and the daily fluctuations in the concentration of sulthiame among children and adults with epilepsy. The evaluation of the sulthiame serum concentrations of 86 patients gave, considering age and comedication, a relatively high correlation (r = 0.82) between the sulthiame dose/body weight and the sulthiame serum concentration. Children on a comparable sulthiame dose per body weight have lower sulthiame concentrations than adults. In our study sulthiame was, with few exceptions, administered in combination with other antiepileptic drugs. The sulthiame serum concentrations were lower in comedication with carbamazepine than with valproic acid. The evaluation of the individual sulthiame dose-level relationship of 8 patients showed in most cases a close and linear relationship. After withdrawal of sulthiame in 11 patients, short elimination half-lives (8.65 +/- 3.10 h) were estimated. This was in accordance with the large daily fluctuations in the sulthiame concentrations (swing: 103.9 +/- 59.3%) of the nine patients examined. The shorter half-lives and higher daily fluctuations in children indicate a higher clearance of sulthiame among children.

Valproic acid-induced carbamazepine-10,11-epoxide toxicity in children and adolescents.

The study of 14 children and adolescents shows that the addition of carbamazepine (CBZ) to a basic valproic acid (VPA) therapy can result in unexpectedly high concentrations of carbamazepine-10,11-epoxide (CE) in the serum (up to 13 micrograms/ml). These concentrations were associated with marked side effects, especially vomiting and tiredness. The concentrations of CBZ were within the therapeutic range. Very high CE concentrations can largely be avoided at the commencement of the CBZ treatment if the CBZ dose is slowly increased. But high CE concentrations (4-8 micrograms/ml) associated with side effects can also be reached in later stages during the build up of CBZ treatment and under steady state conditions. The determination of the CE concentration is important when VPA and CBZ are administered together, especially when side effects occur.

Discontinuation of clonazepam after long-term treatment.

Frequent unwanted side effects and development of tolerance are the main disadvantages of clonazepam (CZP) in long-term treatment of epileptic patients. A review of the literature shows that CZP tolerance more often appears in severe forms of childhood epilepsy (West and Lennox-Gastaut syndromes) than in other epileptic syndromes. We prospectively studied the consequences of CZP discontinuation in 40 consecutive children with difficult-to-treat epilepsies and multiple-drug therapy. The CZP was reduced stepwise in a variable daily reduction rate (0.003-0.16 mg/kg), while serum levels of the comedication were kept unchanged. In only three children (7.5%), CZP was believed to have had some antiepileptic effect; in 30 (75%) it had been ineffective, whereas in six (15%), a decrease in seizure frequency after CZP discontinuation even suggested a negative therapeutic effect. Discontinuation symptoms, mostly in the form of a transitory exacerbation of seizure frequency, occurred in 19 children (47.5%). These children had a significantly higher CZP dose and longer duration of treatment than did children without discontinuation symptoms, but there was no difference between the two groups related to the rate of CZP discontinuance.

Steady-state pharmacokinetics of phenytoin from routinely collected patient data.

Previously reported routine phenytoin clinical pharmacokinetic data from Japan, England, and Germany were analysed to estimate population pharmacokinetic parameters. There were 780 steady-state phenytoin concentrations and associated dosage rates (mg/day) from 322 patients. The patient group spanned paediatric and adult ages, mean age being 18.4 +/- 17.3 (SD) years; 53% were males. The data were analysed using NONMEM, a computer programme designed for population pharmacokinetic analysis. Estimates of the influence of age, gender, data source, height and weight on the maximum elimination rate (Vm) and Michaelis-Menten constant (Km) were obtained. The Vm and Km of a 70 kg adult male European were estimated to be 415 mg/day and 5.7 mg/L, respectively. Vm is not influenced by gender, age or data source. The parameters of a power function of height and weight were estimated to adjust Vm for body size. The best function adjusts Vm in proportion to weight to the 0.6 power; height contains no useful information. Km is not influenced by gender. The Km for patients less than 15 years old is 43% less than that of older patients. The Km of Japanese patients appears to be 23% less than that for European patients. Even after adjustments for age, etc., apparent Vm and Km vary unpredictably among individuals with a coefficient of variation between 10 to 20% and approximately 50% respectively.

Predicting phenytoin dose - a revised nomogram.

The nomogram devised by Richens and Dunlop for predicting phenytoin dose has been tested in 127 residential epileptic patients, and the data obtained were used to prepare a revised version of the nomogram. In a further 78 patients, this new version was found to be superior to the original. The mean Km value was found to be 23.8 mumoles/liter. Km was independent of age and body surface area, but Dmax correlated positively with the latter two variables.

Bioavailability of three phenytoin preparations in healthy subjects and in epileptics.

Serum phenytoin concentrations have been studied in epileptic patients and healthy subjects taking tablets of phenytoin calcium (Desitin), A, phenytoin acid (Desitin), B, and phenytoin acid (Nordmark), C. Retrospective data and prospective investigation of hospitalized patients on long-term phenytoin treatment showed that significantly higher serum concentrations of phenytoin were produced by the phenytoin acid preparations B and C than by the phenytoin calcium preparation A. In a cross over study six volunteers received 200 mg/day of preparations A, B, and C for three weeks. In this study, too, higher phenytoin serum concentrations were produced by B and C than by A, although the differences were not statistically significant. The reasons for the discrepancies between the studies in healthy and epileptic subjects are discussed.

[The spectrogram of trace elements in newborns and infants]. / Uber das Spektrogramm der Spurenelemente bei Neugeborenen und Säuglingen

In 15 newborn infants and 34 sucklings the spectrogram of 25 cations in whole blood, serum and urine was determined by emission and atomic absorption spectrometry. The values ascertained by this method are tabulated and compared with the mean normal values of adults. Already known basic values are supplemented and the distribution patterns of not yet determined trace elements are demonstrated. Highly significant deviations from the normal values of adults were established in the whole blood of the newborn with regard to zinc, copper and chromium. The same differences became manifest when we compared materanal and infantile whole blood. In serum, on the contrary, no differences were observed. In urine, however, significant differences occured in numerous cations. The sucklings of the 1st trimenon showed highly significant deficits in manganese and copper values in whole blood.