The prevalence of epilepsy and pharmacoresistant epilepsy in adults: a population-based study in a Western European country.

PURPOSE: To determine the prevalence of epilepsy in a defined adult population and identify the frequency and principal features of pharmacoresistant epilepsy. METHODS: From a population over 15 years of age residing in a medium-sized French city, all patients with epilepsy on June 30, 1995 were identified from multiple sources. Pharmacoresistance was defined as failure to control epilepsy by at least two first-line antiepileptic drugs, with a seizure frequency of at least one per month for 18 months. Collected data were examined by experts in epileptology, and responding patients were reexamined using a standardized diagnostic questionnaire. ILAE definitions and classifications were used. RESULTS: The age-adjusted prevalence of active epilepsy was 5.4 per 1,000 (95% CI: 4.7-6.0) and was higher for males (7.8) than for females (5.2). For epilepsy in remission under treatment, this rate was 0.7 per 1,000 (95% CI: 0.5-0.95). Age-specific prevalence was highest in age groups 25-49 years and declined in the oldest age groups. Localization-related seizures represented 61.1% of cases and generalized seizures 30.9%. The proportion of noncontrolled epilepsy (seizure-frequency at least one per month for 18 months) was 15.6%, corresponding to a prevalence of 0.94 per 1,000. In this group, the mean age at onset was lower (p = 0.0007) and localization-related epilepsy more frequent (p = 0.01). CONCLUSION: The findings support previous epidemiological estimates of the prevalence of epilepsy in developed countries. For approximately one patient in eight, epilepsy was not adequately controlled.

Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy.

Previous studies from our group, focusing on neuro-glial remodelling in human temporal lobe epilepsy (TLE), have shown the presence of immature vascular cells in various areas of the hippocampus. Here, we investigated angiogenic processes in hippocampi surgically removed from adult patients suffering from chronic intractable TLE, with various aetiologies. We compared hippocampi from TLE patients to hippocampi obtained after surgery or autopsy from non-epileptic patients (NE). We quantified the vascular density, checked for the expression of angiogenic factors and their receptors and looked for any blood-brain barrier (BBB) leakage. We used a relevant model of rat limbic epilepsy, induced by lithium-pilocarpine treatment, to understand the sequence of events. In humans, the vessel density was significantly higher in TLE than in NE patients. This was neither dependent on the aetiology nor on the degree of neuronal loss, but was positively correlated with seizure frequency. In the whole hippocampus, we observed many complex, tortuous microvessels. In the dentate gyrus, when the granular layer was dispersed, long microvessels appeared radially orientated. Vascular endothelial factor (VEGF) and tyrosine kinase receptors were detected in different types of cells. An impairment of the BBB was demonstrated by the loss of tight junctions and by Immunoglobulines G (IgG) leakage and accumulation in neurons. In the rat model of TLE, VEGF over-expression and BBB impairment occurred early after status epilepticus, followed by a progressive increase in vascularization. In humans and rodents, angiogenic processes and BBB disruption were still obvious in the chronic focus, probably activated by recurrent seizures. We suggest that the persistent leakage of serum IgG in the interstitial space and their uptake by neurons may participate in hypoperfusion and in neuronal dysfunction occurring in TLE.

Increased number of neural progenitors in human temporal lobe epilepsy.

An increased neurogenesis is reported in animal models of mesial temporal lobe epilepsy (MTLE) but the fate of newborn cells is unknown. Here, we attempted to demonstrate neurogenesis in adult epileptic tissue obtained after hippocampectomy. MTLE hippocampi showed increased expression of division markers and of Musashi-1, a marker of neural progenitors, compared to control hippocampi. Large quantities of Musashi-1+ cells were obvious in the subgranular layer and the subventricular zone, both known neurogenic areas, and in the fissura hippocampi. Musashi-1 was expressed by small cells that were mainly vimentin+ or nestin+, rarely Dcx+ or PSA-NCAM+ and negative for markers of mature neurons or astrocytes. Some of them are present in the granular layer, the hilus, and CA1 area resembling the ectopic positions described in rodents. These findings demonstrate that neural progenitors proliferate in chronic epilepsy and suggest that the fissura hippocampi behaves like another neurogenic area.

Psychometric validation of the French version of the side-effects and life satisfaction inventory (SEALS) in epileptic patients: comparison with the QOLIE-31 inventory and a generic quality of life questionnaire.

A psychometric evaluation of a French version of the side-effects and life satisfaction inventory (SEALS) was carried out. SEALS was compared to the quality of life in epilepsy-31 questionnaire (QOLIE-31) and a generic, health-related quality-of-life questionnaire, the Nottingham health profile (NHP). The psychometric properties of SEALS, assessed in 190 adult subjects with epilepsy, included: acceptability, test-retest reliability and validity, multitrait analysis including internal consistency and item-to-scale correlations, construct validity using factor analysis and discriminative validity using associations with disease characteristics and treatment effects, and, correlations with NHP and QOLIE-31 scores for convergent and divergent validity. Both acceptability and reproducibility were good and internal consistency was high (Cronbach's alpha coefficient = 0.92). Factor analysis with varimax rotation identified five factors: the first, related to cognitive function accounted for 26.0% of the variance. Discriminative validity was good for most treatment characteristics (tolerability, seizure control, compliance) and clinical features (epilepsy type, seizure frequency and severity, depressive symptoms). Correlations with the NHP and QOLIE-31 scores were consistently strong. It was concluded that the psychometric properties of the French translation of SEALS were similar to the original English version. In addition, SEALS provides information on quality of life that is complementary to that obtained with QOLIE-31. In particular, with respect to the QOLIE-31, the SEALS provides information on cognitive and neuropsychological aspects of impairment of quality of life, whereas the QOLIE-31 has a broader scope, taking into account multiple aspects of quality of life in epilepsy.

GABA receptor 1 polymorphism (G1465A) and temporal lobe epilepsy.

PURPOSE: To reevaluate the genetic contribution of the polymorphism G1465A of the gene coding for gamma-aminobutyric acid (GABA)(B) receptor 1 subunit [GABA(B)(1)] in a sample of French patients with temporal lobe epilepsy (TLE) and to perform an exploratory analysis in other phenotypic subgroups. METHODS: The 134 patients were genotyped for the polymorphism G1465A. This sample was divided in two groups. The first one had patients with nonlesional TLE, and the second one, with lesional TLE. Then these two groups were compared with a sample of 145 healthy individuals. RESULTS: The genotype and allele distributions for the polymorphism G1465A showed no difference between patients and controls. CONCLUSIONS: The association between the variant G1465A and the sample of patients could not be replicated, so these results exclude a major effect of this polymorphism in the susceptibility to nonlesional TLE. Larger samples should be tested to determine whether the G1465A in exon 7 of the GABA(B)(1) receptor gene is a susceptibility factor for nonlesional TLE.

Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies.

PURPOSE: Several studies have shown that carbamazepine (CBZ) may aggravate idiopathic generalized epilepsy (IGE). Oxcarbazepine (OXC) is a new drug chemically related to CBZ. We report six cases of juvenile IGE with a clear aggravation by OXC. METHODS: We retrospectively studied all patients with IGE first referred to our epilepsy department between January 2001 and June 2003 and treated with OXC. RESULTS: During this period, six patients were identified. All had an aggravation of their epilepsy in both clinical and EEG activities. OXC had been used because of an incorrect diagnosis of focal epilepsy or generalized tonic-clonic seizures (GTCSs) of undetermined origin (no syndromic classification of the epilepsy). Before OXC, only one patient had experienced a worsening of seizures with an inadequate drug (CBZ). Four had juvenile myoclonic epilepsy, one had juvenile absence epilepsy, and one had IGE that could not be classified into a precise syndrome. OXC (dosage range, 300-1,200 mg/day) was used in monotherapy in all of them except for one patient. Aggravation consisted of a clear aggravation of myoclonic jerks (five cases) or de novo myoclonic jerks (one case). Three patients had exacerbation of absence seizures. One patient had worsened dramatically and had absence status, and one had de novo absences after OXC treatment. The effects of OXC on GTCSs were less dramatic, with no worsening in frequency in three and a slight increase in three. CONCLUSIONS: OXC can be added to the list of antiepileptic drugs that can exacerbate myoclonic and absence seizures in IGE.

Psychometric validation of the French version of the quality of life in epilepsy inventory (QOLIE-31): comparison with a generic health-related quality of life questionnaire.

A psychometric evaluation of a French transcultural version of the quality of life in epilepsy inventory-31 (QOLIE-31) was carried out. QOLIE-31 was compared to a generic health-related quality of life questionnaire, the Nottingham health profile (NHP). The psychometric properties of QOLIE-31, assessed in 190 adults with epilepsy, included: acceptability, test-retest reliability and validity (multi-trait analysis including internal consistency and item-to-scale correlations, construct validity using factor analysis, discriminative validity using relationship with disease characteristics, treatment effects, divergent and convergent validity using correlations with NHP scores). Both acceptability and reproducibility were good and internal consistency was high (Cronbach's alpha coefficient = 0.86). Factor analysis with varimax rotation identified seven factors with eigenvalues > 1, with two factors, related to cognitive function and mood, accounting for 46.5% of the variance. However, goodness of fit indices revealed that a model with four factors best fitted the data. The first factor corresponds to a generic mental dimension, the second is equivalent to the cognitive functioning dimension, the third to medication effects including social functioning, and the fourth to seizure worry. Discriminative validity was good for seizure control and treatment tolerability. High correlations between QOLIE-31 and pertinent NHP scales (emotional reactions, energy and social isolation) were observed. The French version of QOLIE-31 thus meets established psychometric criteria for reliability and validity.

Wicket spikes during rapid eye movement sleep.

Wicket spikes correspond to a normal variant activity. They usually occur in adults over 50 years of age during drowsiness and light nonrapid eye movement (NREM) sleep. No data exist in the precise distribution of this activity during all the different sleep stages, particularly during rapid eye movement (REM) sleep. The authors report five observations of persistence of this activity during REM sleep. Only one patient was over 50 years of age. The authors found a predominant expression on one temporal side, but inconsistently on the left side (three on the left side versus two on the right side). Wicket spikes always persist in REM sleep. They have an identical morphology as drowsiness or stage 2 sleep. There were no changes in their location. The authors found no correlation with the tonic or phasic phases of REM sleep.

Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis.

Many experimental studies suggest that NFkappaB, a transcription factor involved in acute inflammation, and cytokines participate in neuronal excitability and/or glial scar formation in epilepsy. In this report, we looked for the expression of NFkappaB in hippocampi surgically removed in patients with medial temporal lobe epilepsy (MTLE) and hippocampal sclerosis (HS) who had an history of febrile convulsions. We analyzed 18 hippocampi from epileptic patients with MTLE and HS, and we used as control specimens three hippocampi from non-epileptic patients and four hippocampi from patients with cryptogenic MTLE without HS. We used antibodies raised against the NFkappaB-p65 subunit and we identified glial cells with specific antibodies. Hippocampi from patients with MTLE and HS displayed severe neuronal loss surrounded by gliosis in CA1 area and more or less in CA3/CA4 areas. Double immunolabeling showed that reactive astrocytes of lesioned areas over-expressed NFkappaB-p65 (significantly when compared to control specimens). Moreover, some surviving pyramidal neurons in these areas and numerous dentate granule cells were strongly positive for NFkappaB-p65 in cytoplasm and nucleus, whereas control hippocampi showed a faint basal cytoplasmic staining in neurons. These results suggest that in epileptic hippocampi with typical sclerosis, inflammatory processes are chronically active or transiently re-induced by recurrent seizures. Whether NFkappaB over-expression reflects protective or deleterious mechanisms in the epileptic focus remains to be elucidated.

Haplotype study of West European and North African Unverricht-Lundborg chromosomes: evidence for a few founder mutations.

Unverricht-Lundborg disease (ULD) is a progressive myoclonus epilepsy common in Finland and North Africa, and less common in Western Europe. ULD is mostly caused by expansion of a dodecamer repeat in the cystatin B gene ( CSTB) promoter. We performed a haplotype study of ULD chromosomes (ULDc) with the repeat expansion. We included 48 West European Caucasian (WEC) and 47 North African (NA) ULDc. We analysed eight markers flanking CSTB(GT10-D21S1890-D21S1885-D21S2040-D21S1259- CSTB-D21S1912-PFKL-D21S171) and one intragenic variant in the CSTB 3' UTR (A2575G). We observed a founder effect in most of the NA ULD patients, as 61.7% of the NA ULDc (29/47) shared the same haplotype, A1 (1-1-A-1-6-7), for markers D21S1885-D21S2040-A2575G-D21S1259-D21S1912-PFKL. Moreover, if we considered only the markers D21S1885, D21S2040, A2575G and D21S1259, 43 of the 47 NA ULDc shared the same alleles 1-1-A-1, haplotype A. As previously shown, the WEC ULDc were heterogeneous. However, the Baltic haplotype, A3 (5-1-1-A-1-1), was observed in ten WEC ULDc (20.8%) and the CSTB 3'UTR variant, which we called the Alps variant, was observed in 17 ULDc (35.4%). Finally, as almost all NA patients, like Scandinavian patients, were of the haplotype A, we assumed that there was an ancient common founder effect in NA and Baltic ULD patients. We estimated that the putative most recent common ancestral ULD carrier with this haplotype A must have existed about 2,500 years ago (100-150 generations). Finally, this work provides evidence for the existence of only a small number of founder mutations in ULD.

Immature-like astrocytes are associated with dentate granule cell migration in human temporal lobe epilepsy.

In human temporal lobe epilepsy, a dispersion of dentate granule cells is frequently described in adults who had an early risk factor. To elucidate the role of glia in this phenomenon, we investigated neuronal dispersion, astrocyte organization and expression of intermediate filaments of mature and immature astrocytes (i.e. glial fibrillary acidic protein (GFAP) and vimentin, respectively) in seven subjects with early febrile seizures (F(+)) and five subjects with other etiologies than febrile seizures (F(-)). Compared to F(-) patients, a majority of F(+) subjects showed neuronal dispersion and vimentin expression in radial glia. However, in two patients with the maximal dispersion, radial processes expressed only GFAP. We suggest that granule cell migration that occurs in adult epileptic focus results from the transient occurrence of immature-like glia throughout the granular layer.