Mogens Laue Friis

Which seizure-precipitating factors do patients with epilepsy most frequently report?

When treating patients with epilepsy, dealing with seizure-precipitating factors is a partly neglected and underestimated supplement to more traditional therapies. The aim of this study was to investigate the incidence of seizure precipitants in a large epilepsy population and to determine which precipitants patients most often reported. Study participants included twins and their family members ascertained from the Norwegian Twin Panel (NTP), the Danish Twin Registry (DTR), and the Mid-Atlantic Twin Registry (MATR). One thousand six hundred seventy-seven patients with epilepsy were identified and were asked about seizure precipitants using a closed-ended questionnaire. Fifty-three percent reported at least one seizure-precipitating factor, while 30% claimed to have experienced two or more such factors. Emotional stress, sleep deprivation, and tiredness were the three most frequently reported precipitants. Patients with generalized seizures seemed to be more sensitive to sleep deprivation and flickering light than those with partial seizures, while women with partial seizures appeared to be more prone to seizures during menstruation than women with generalized seizures. Knowledge of seizure precipitants has practical implications, not only in patient treatment and counseling, but also for diagnosis, in that it may be helpful in facilitating the appearance of interictal epileptiform discharges in EEG and ictal EEG recordings.

Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment

Efficacy and tolerability of the new antiepileptic drug oxcarbazepine, was evaluated in a retrospective multicentre study. The records of all 947 epilepsy patients treated with oxcarbazepine in the eight participating centres from 1981 through 1990 were examined. The median daily dose of oxcarbazepine was 30 mg/kg in children, 18 mg/kg in adults, and 15 mg/kg in elderly patients, given b.i.d. or t.i.d. The mean plasma levels of the main active metabolite of oxcarbazepine was 88, 79, and 68 μmol/l in children, adults, and elderly, respectively. In patients shifted to oxcarbazepine treatment, seizure frequency was unchanged in 51‐66%, 32‐48% had a decrease, and 1‐10% an increase in seizure frequency, considering the individual seizure types separately. Adverse events were reported in one third of patients, most frequently affecting the CNS (dizziness: 6%; sedation: 6%; fatigue: 6%). Rash was reported in 6% of patients, half of these patients had previously had an allergic reaction to carbamazepine. Hyponatremia was found in about a quarter of the patients from whom data were available. No congenital malformations were seen in nine live‐born, first trimester oxcarbazepine‐exposed children.

Gender Differences in Epilepsy

Summary:  Purpose: The aim of this study was to look at gender differences in unselected populations of patients with epilepsy classified according to the 1989 International League Against Epilepsy (ILAE) criteria.

Genetic and environmental factors in epilepsy: a population-based study of 11 900 Danish twin pairs

The contribution of genetic and environmental factors to the occurrence of epilepsy was examined in an unselected sample of twins recruited from the population-based Danish Twin Registry. Information on the occurrence of epilepsy in both members of a twin pair was obtained from 11900 pairs whose ages ranged from 12 to 41 years. Concordance rates, odds ratios and tetrachoric correlations were used to quantify the similarity of monozygotic (MZ) and dizygotic (DZ) twins. The sample was stratified by sex and separated into two age cohorts for analysis. Significantly higher probandwise concordance rates were found for MZ compared with DZ twins (0.37 and 0.08, P<0.01). Odds ratios and tetrachoric correlation showed similar pattern. An etiological model including additive genetic and individual specific environmental factors provided the best overall fit to the data, with 70 and 88% of the liability to develop epilepsy being accounted for by genetic factors in the younger and older cohorts, respectively. Individual specific environmental factors explained the remaining 30 and 12%, respectively. In conclusion, this study has confirmed the substantial impact, which genetic factors have in the etiology of epilepsy. The heritability of epilepsy is high and seems to increase with age.

Epileptic seizures and syndromes in twins: the importance of genetic factors

The role of genetic factors in the occurrence of epilepsy syndromes was studied in twins recruited from the population-based Danish Twin Registry. A total of 34,076 twins were screened for epilepsy. Cases were confirmed and classified by two neurologists according to the classification systems of the International League Against Epilepsy (ILAE). A total of 214 twin pairs with epileptic seizures and 190 pairs with epilepsy were ascertained. Significantly higher concordance rates were found for monozygotic (MZ) compared to dizygotic (DZ) twins for both epileptic seizures (0.56 for MZ and 0.21 for DZ pairs, P<0.001) and for epilepsy (0.49 for MZ and 0.16 for DZ pairs, P<0.001). Concordance rates were also higher for MZ twins compared to DZ twins for both generalized epilepsy (0.65 for MZ and 0.12 for DZ) and for localization-related epilepsy (0.30 for MZ and 0.10 for DZ). In twin pairs where both members had seizures, 83% of MZ and 65% of DZ pairs had the same major epilepsy syndrome. Genetic factors were found to account for 80% of the liability to both epileptic seizures and epilepsy. In conclusion, analysis of this neurologist-verified epilepsy twin data set has confirmed that genetic factors have a substantial impact on the etiology of epileptic seizures as well as on the occurrence of both generalized and partial epilepsies.

Genetic and environmental factors in febrile seizures: a Danish population-based twin study

The relative importance of genetic and environmental factors in the etiology of febrile seizures was estimated using a large, unselected population-based twin sample. A total of 34,076 twins (aged 12-41 years), recruited from the Danish Twin Registry, were screened for febrile seizures by questionnaire. Information was obtained from 11,872 complete pairs. Concordance rates, odds ratios and correlations were used to assess the degree of similarity in monozygotic (MZ) and dizygotic (DZ) twins. Model fitting and estimation of heritability (proportion of the population variance attributable to genetic variation) were performed using standard biometrical methods. Significantly higher probandwise concordance rates were found for MZ compared with DZ twins (0.36 and 0.12, P < 0.01). Odds ratios and correlations showed a similar pattern. An etiological model including additive genetic effects and individual-specific environmental factors provided the best fit to the data with a heritability for febrile seizures of 70% (95% CI: 61-77%). The remaining 30% of the variation could be attributed to individual-specific environmental factors. In conclusion, this study has confirmed a major impact of genetic factors in the etiology of febrile seizures. Future studies aimed at identifying the specific genetic factors and environmental exposures involved in determining febrile seizure risk are clearly warranted.

Antiepileptic drug utilization: a Danish prescription database analysis

Objectives– The purpose of the study was to use prescription data from a Danish database to analyse and evaluate antiepileptic drug (AED) utilization, and compare with other prevalence studies. Methods– A Danish research database covering outpatient prescription data from a population of 471,873 persons was used. Prescription records on all patients prescribed AEDs during 1998 were retrieved. A cohort was extracted from the group of AED users. Results– We identified 5426 AED users. A total of 3756 of the 5426 AED users were included in our cohort. Of the subjects in the cohort 74% were on monotherapy, 19% used two AEDs and only 7% used three or more AEDs. The eight most frequent regimens were all monotherapy: carbamazepine, oxcarbazepine, phenobarbital, valproic acid, lamotrigine, clonazepam, phenytoin and primidon in that order. The estimated crude 1‐year prevalence of AED use was 0.77% for women and 0.83% for men (P<0.001), and it increased with age for both genders. Conclusions– The prescription pattern reported here is in accordance with the general guidelines for the treatment of epilepsy in Denmark, except for a surprisingly extensive use of phenobarbital. With specific reservations the figures appear to be reasonable estimates of the prevalence of epilepsy.

Facial clefts in sibs and children of epileptic patients

The prevalence of facial clefts in sibs and children of 2,072 epileptics ascertained in a defined region was determined by record linkage with a national cleft register, which also provided expected figures. Observed/expected ratios were increased only for cleft lip with or without cleft palate if the mother had manifested epilepsy: it was 4.7 when anticonvulsants were given before and during pregnancy, 2.7 in cases with no treatment, and zero in children born prior to maternal epilepsy. Children of epileptic men and sibs of epileptics showed no increase. The prevalence of isolated cleft palate was not above expectation in any group.

Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14

A previous study of 34 nuclear pedigrees segregating juvenile myoclonic epilepsy (JME) gave significant evidence of linkage with heterogeneity to marker loci on chromosome 15q13-14 close to the candidate gene CHRNA7 (Hum. Mol. Genet. 6 (1997) 1329). The aim of this work was to further evaluate the putative aetiological role of CHRNA7 in JME within the 34 families originally described, and to assess the contribution of this locus to a broader phenotype of idiopathic generalised epilepsy (IGE). Multipoint linkage analysis and intrafamilial association studies were performed with microsatellite markers that encompass both CHRNA7 and its partial duplication (CHRFAM7A). A maximum HLOD of 3.45 [alpha=0.58; (Zall=2.88, P=0.0008)] was observed 8 cM distal to D15S1360, a CHRNA7 intragenic marker. Significant exclusion lod scores were obtained across the region in 12 mixed phenotype JME/IGE families. Mutation screening of the CHRNA7 gene (and consequently exons 5-10 of CHRFAM7A) and its putative promoter sequence identified a total of 13 sequence variants across 23 of 34 JME-affected families. Two variants (c.1354G>A and c.1466C>T) are predicted to result in amino acid changes and one (IVS9+5G>A) is predicted to result in aberrant transcript splicing. However, none of the variants alone appeared either necessary or sufficient to cause JME in the families in which they occurred. In conclusion, linkage analyses continue to support the existence of a locus on chromosome 15q13-14 that confers susceptibility to JME but not to a broader IGE phenotype. Causal sequence variants in the positional candidate CHRNA7 have not been identified but the presence of multiple segmental duplications in this region raises the possibility of undetected disease-causing genomic rearrangements.

Linkage and mutational analysis of CLCN2 in childhood absence epilepsy

In order to assess the chloride channel gene CLCN2 as a candidate susceptibility gene for childhood absence epilepsy, parametric and non-parametric linkage analysis was performed in 65 nuclear pedigrees. This provided suggestive evidence for linkage with heterogeneity: NPL score=2.3, p<0.009; HLOD=1.5, alpha=0.44. Mutational analysis of the entire genomic sequence of CLCN2 was performed in 24 unrelated patients from pedigrees consistent with linkage, identifying 45 sequence variants including the known non-synonymous polymorphism rs2228292 (G2154C, Glu718Asp) and a novel variant IVS4+12G>A. Intra-familial association analysis using the pedigrees and a further 308 parent-child trios showed suggestive evidence for transmission disequilibrium of the G2154C minor allele: AVE-PDT chi(1)2 = 5.17, p<0.03. Case-control analysis provided evidence for a protective effect of the IVS4+12G>A minor allele: chi(1)2 = 7.27, p<0.008. The 65 nuclear pedigrees were screened for three previously identified mutations shown to segregate with a variety of idiopathic generalised epilepsy phenotypes (597insG, IVS2-14del11 and G2144A) but none were found. We conclude that CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy.