Mogens Dam

Double-Blind, Placebo-Controlled Trial of Topiramate as Add-On Therapy in Patients with Refractory Partial Seizures

Summary: In a double‐blind, randomized, parallel‐group trial, we compared topiramate (TPM) with placebo as addon therapy in patients with refractory partial epilepsy. TPM was titrated either to the target dosage of 800 mg/ day [400 mg twice daily (b. i. d.)] or to the maximal tolerated dose if lower. Twenty‐eight (28) patients were randomized to each treatment group. In the intent‐to‐treat analysis, the net median percent reduction relative to placebo in average monthly seizure rate was 54% for patients in the TPM group (p < 0.001). None of the placebo‐treated patients and 43% of the patients treated with TPM experienced 250% reduction in seizures (p = 0.001), and 36% of patients assigned to TPM had a 75–100% reduction in seizures (p < 0.01). Secondarily generalized seizures were also significantly reduced in the TPM group (p = 0.044). The most common adverse events (AE) reported in the TPM group were fatigue, impaired concentation, weight loss, dizziness, and paresthesias. AE occurring either during the rapid titration of TPM or at high dosages led 21% of TPM‐treated patients to withdraw from the study. Half of these occurred during the titration study period. No serious AE or clinically important changes in clinical laboratory measures were observed. The present study further establishes the favorable profile and good benefithisk ratio of TPM in resistant partial epilepsy.

Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy

BACKGROUND Valproate is used widely for the treatment of epilepsy but has been associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. The mechanism for these associations is unknown, but they have been hypothesized to be secondary to valproate-associated weight gain. This study was conducted to test the hypothesis that the antiepileptic drug lamotrigine, which also has a broad spectrum of anti-seizure efficacy, would not be associated with endocrine abnormalities and would not cause weight gain. OBJECTIVE AND METHODS This open-label, cross-sectional study compared (1) endocrine and lipid measures during the early follicular phase of the menstrual cycle; (2) prevalence of menstrual disorders (from patient diaries recorded over three cycles); and (3) body weight of women with epilepsy on lamotrigine monotherapy (n=119) with those on valproate monotherapy (n=103) for <5 years. RESULTS Mean total serum testosterone and androstenedione levels were higher (P<0.02) in the valproate group compared with the lamotrigine group. More lamotrigine patients (87%) than valproate patients (77%) reported regular menstrual cycles at the Screening Visit. The prevalence of anovulation did not differ between lamotrigine and valproate. Mean HDL cholesterol levels were higher (P<0.01) with lamotrigine compared with valproate as were LDL and total cholesterol levels (P<0.05). Mean total insulin levels did not significantly differ between the groups. Whereas mean body weight in lamotrigine patients did not differ between the time lamotrigine treatment was initiated and the Study Visit, mean weight in valproate patients increased by 3.7 kg. CONCLUSIONS Compared with lamotrigine monotherapy, valproate monotherapy was associated with weight gain and higher androgen levels in women with epilepsy. These data suggest that the hyperandrogenism observed in some women using valproate for epilepsy may be secondary to drug therapy. Lamotrigine monotherapy may be more appropriate than valproate for women in whom reproductive endocrine or metabolic abnormalities are potential concerns, i.e. women with concerns about weight gain, diabetes, hirsutism, polycystic ovary syndrome, menstrual dysfunction or infertility.

Public attitudes toward epilepsy in Denmark

Summary: Social acceptance of persons with epilepsy very often constitutes a considerable problem for patients and their relatives. Nationwide opinion polls on the knowledge of and public attitude toward epilepsy have been taken in several countries, but never in Denmark. We report a Gallup survey of the general knowledge of and attitude toward epilepsy. A representative population of 1,500 persons aged ≥15 years was selected in a four‐state proportional sampling procedure. Ninety‐seven percent of respondents had heard or read about epilepsy, 60% of these knew a person with epilepsy, and 50% had seen an epileptic seizure. The attitudes toward social acceptance and employment of persons with epilepsy were generally favorable, but 7% had objections to social contact between their children and persons with epilepsy in the playground and at school and 7% had objections to equal employment. Familiarity with persons with epilepsy was correlated to questions about attitudes and general knowledge of epilepsy. Such knowledge and public attitude in Denmark are mainly positive, but we believe that a continuous information campaign about epilepsy is essential, especially among youth.

Gamma-vinyl-GABA: A single-blind trial in patients with epilepsy

ABSTRACT The anti‐epileptic effect of gamma‐vinyl‐GABA (GVG) was studied using a placebo‐controlled, single‐blind design in 15 patients with therapy‐resistant epilepsy, the majority experiencing complex partial seizures. GVG was added to concomitant treatment, which was kept at constant serum levels. Following administration of 1 g, 2 g and 3 g per day, significant reductions in seizure frequency were observed. A poor correlation was found between GVG serum levels and clinical effect. Only mild and transient side‐effects were observed.

Adjunctive treatment of partial seizures with tiagabine: A placebo-controlled trial

Tiagabine is a new antiepileptic drug which acts by a novel mechanism, inhibiting the reuptake of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into neurons and glia. A double-blind, placebo-controlled, crossover trial was undertaken, based upon a response-dependent design. Ninety-four patients with complex partial seizures with or without secondary generalised tonic-clonic seizures were recruited into an open screening phase and tiagabine was added to their existing drug therapy in doses titrated to reduce seizure frequency by > or = 25% or to the limit of tolerance. Forty-six responders were subsequently randomised to a double-blind crossover trial in which tiagabine was compared with placebo. Forty-two patients completed the trial. A significant reduction in the frequency of complex partial and secondary generalised tonic clonic seizures was seen. Twenty-six percent had a reduction of > or = 50% in the frequency of their complex partial seizures, and of the 27 patients who also had secondary generalised tonic clonic seizures, 63% experienced a reduction of > or = 50%. No interactions with baseline antiepileptic drugs were detected and no serious adverse reactions occurred. The commonest adverse events were tiredness, dizziness and headache. We conclude that tiagabine has promising antiepileptic effects. Further trials are underway.

PHENYTOIN and PHENOBARBITONE PLASMA CLEARANCE DURING PREGNANCY

In a retrospective investigation the plasma level of phenytoin (DPH) and phenobarbitone (PB) was studied in 23 epileptics during and outside pregnancy to elucidate the possible influence of pregnancy on drug metabolism, and to correlate changes in seizure frequency to plasma clearance. the plasma clearance was expressed as the ratio between dose in mg per 24 hours, and the plasma level in mg per liter. In all the patients, plasma clearance of DPH increased during pregnancy with interindividual differences. Within a few months after the delivery most patients had DPH plasma clearance in the same range as before pregnancy. the change in PB plasma clearance was insignificant. the increase in seizure frequency seemed to be correlated to the increased DPH plasma clearance. It is therefore recommended that the DPH plasma levels be monitored once a month during pregnancy and after the delivery, until the previous plasma clearance rate is reached, in order to adjust the plasma levels to within the therapeutic range. It might then be possible to prevent the increased seizure frequency which is seen in 45 per cent of pregnant epileptics.

No influence of the antidepressant paroxetine on carbamazepine, valproate and phenytoin

A single-blind, placebo-controlled, cross-over trial investigating possible interactions between paroxetine, a serotonin re-uptake inhibitor, and carbamazepine (CBZ), valproate (VPA) and phenytoin (PHT) was carried out in 20 outpatients with epilepsy. Patients on long-term treatment with CBZ, VPA, or PHT were given a 7-day placebo treatment, followed by paroxetine co-treatment for 16 days. Side effects were infrequent and mild. Paroxetine caused no changes in the plasma concentrations and all values were within the recommended ranges. No changes in protein binding were found. Plasma concentrations of paroxetine at steady state (8-147 ng/ml) were in the normal range for a 30-mg daily dosing regimen. None of the patients experienced epileptic seizures during the study.

The Epileptic Mother and Her Child

Summary: This study is a review of the literature on the influence of epilepsy and antiepileptic medication on the course of pregnancy and the foetus, as well as of the effect of pregnancy on the disease. Antiepileptic treatment is supposedly responsible for the increased rate of abnormal bleeding after delivery. Data on the perinatal mortality of epileptics are conflicting. The offspring of epileptic women are often smaller than normal neonates, indicating retarded growth, and the incidence of malformations is 1.25 times higher. Until now there has been no direct evidence of a teratogenic effect of the commonly used antiepileptic drugs, and the risk of malformations may possibly be correlated to the severity of the epilepsy and the disease per se. The effect of pregnancy on seizure frequency seems to be quite variable. Higher seizure frequency is seen during pregnancy, but this is not a universal phenomenon. The incidence of seizures in gestational epilepsy has no predictive value concerning the course of later pregnancies. A positive correlation seems to exist between the development of eclampsia and later epilepsy, a family history of epilepsy and cerebral dysrhytmias. Status epilepticus is uncommon in pregnancy. The requirement of several antiepileptic drugs is increased during pregnancy. And the metabolism of carbamazepine, primidone, and clorazepate is probably accelerated in the gestational period. Data on the metabolism of other antiepileptic drugs in this situation are inconclusive or lacking. The intestinal absorption of antiepileptic drugs may be impaired during pregnancy. The reduced concentration of plasma proteins is probably only of minor importance. Placentally transferred antiepileptic drugs are usually cleared from the newborn within a week, but a risk of intoxication in the newborn exists when diazepam is administered to the mother at delivery. The concentration of antiepileptic drugs in breast milk is low, but careful observation of the newborn is important when this drug and phenobarbitone are administered to the mother. The epileptic pregnant woman demands special attention, including careful obstetric control and monitoring of plasma concentrations once a month during pregnancy and once a week post partum until plasma clearance has returned to prepregnancy values with subsequent dose adjustment. Close observation of the newborn is mandatory. In most instances, breast‐feeding can be carried out without any risk to the baby.

Cognitive function and anticonvulsant therapy: effect of monotherapy in epilepsy.

Introduction– The effect of antiepileptic drugs (AED) on cognitive function was studied in 87 patients with epilepsy. Material and methods– Group A: (n = 52) started AED treatment (carbamazepine, oxcarbazepine, sodium‐valproate, phenobarbital or phenytoin). Group B: (n = 27) had AED monotherapy withdrawn (carbamazepine or sodium‐valproate). Group C: (n = 8) was switched from phenytoin to carbamazepine monotherapy. The patients were tested before and 4 months after change of the treatment. Results– In group A the test performances were in general unchanged. Patients who had their drug treatment withdrawn (group B) and the patients who were switched from phenytoin to carbamazepine (group C) improved in single tests. The predominant changes in performance seem to be due to practice effect. Conclusion– Cognitive functions are only minimally influenced by AEDs after short‐term treatment whereas there is a slight improvement after discontinuation of long‐term administration of carbamazepine and valproate. A lack of practice effect might be the first indicator of a negative effect of AED on cognitive function.

Pregnancy and epilepsy: a retrospective study of 151 pregrancies

Objective– We studied the course of pregnancy in women with epilepsy to identify possible risk factors which might complicate the epilepsies and pregnancy outcomes. Material and methods– Data were collected retrospectively from the records of 151 pregnancies in 124 women with epilepsy from 1978–1992. Epilepsy variables were compared with that of non‐pregnant women with epilepsy mached for age. Obstetric and neonatal variables were compared with those of all deliveries in the same unit from 1979–1992 (n=38.983). Results– Pregnancy among patients with epilepsy was more likely to occur in women with relatively mild epilepsy. In 12% of the pregnancies, the women were untreated while 71% were on monotherapy. Twenty‐one percent had increased seizure frequency during the pregnancy. Perinatal deaths among newborns of epileptic mothers (1.3%) was more frequent but not significantly increased compared to the background population of 0.5% (95% CI 0.2–4.7). A total of 5.3% had congenital malformations compared to 1.5% in the controls (95% CI 2.3–10.3). No neural tube defects were observed. Maternal treatment with phenytoin was significantly related to the occurrence of congenital malformations, P=0.04. Conclusions– Most women with epilepsy have an uncomplicated pregnancy and normal healthy offsprings. Maternal treatment with phenytoin might be associated with congenital malformations. No other risk factors could be identified.