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At least 19 recordsLinked to original sources
PubMed1998

Aggravation of generalized epilepsies.

Generalized epilepsies are treatable with a number of antiepileptic drugs (AEDs) that are effective in different seizure types and epilepsy syndromes. The mechanisms of action of these AEDs are incompletely understood but include inhibition of low-threshold calcium currents and of voltage-gated sodium channels and facilitation of GABA(A) receptor currents. The mechanisms of aggravation are also unknown but could include elevation of brain GABA, blockade of voltage-gated sodium channels, and idiosyncratic toxicity reactions. Anecdotal reports suggest that aggravation of generalized epilepsy can occur with virtually all AEDs. The best-documented examples are aggravation of absences by carbamazepine and aggravation of symptomatic generalized epilepsies by vigabatrin. Therefore, the physician must be constantly aware of the problem of aggravation of seizures by AEDs. With careful diagnosis of the epileptic syndrome and an awareness of the problem, aggravation of seizures can be minimized.

Acute Disease↗
PubMed2003

From molecules to networks: cortical/subcortical interactions in the pathophysiology of idiopathic generalized epilepsy.

Generalized epilepsy involves abnormally synchronized activity in large-scale neuronal networks. Burst firing of action potentials is a potent mechanism for increasing neural synchrony and is thought to enhance cortical and thalamic rhythmic network activity. Absence seizures, a form of generalized epilepsy, occur in children as brief 5- to 10-s periods of behavioral arrest associated with massive 3- to 4-Hz spike-wave discharges in cortical and thalamic networks. Prior research has shown that enhanced burst firing may be crucial for the transition from normal to epileptic activity. Can enhanced burst firing in one region of the nervous system, such as the cortex, transform the entire thalamocortical network from normal activity to spike-and-wave seizures? Enhanced burst firing in corticothalamic neurons may increase gamma-aminobutyric acid-B (GABAB) receptor activation in the thalamus, leading to the slower, more synchronous oscillations seen in spike-and-wave seizures. Does "generalized" spike-wave activity homogeneously involve the entire brain, or are there crucial nodes that are more important than others for the generation and behavioral manifestations of generalized seizures? Animal and human data suggest that so-called generalized seizures involve selective thalamocortical networks while sparing others. A greater understanding of these molecular and network mechanisms will ultimately lead to improved targeted therapies for generalized epilepsy.

Animals↗
PubMed2005

Juvenile myoclonic epilepsy--a generalized epilepsy syndrome?

Juvenile myoclonic epilepsy (JME) has been classified as a syndrome of idiopathic generalized epilepsy and is characterized by specific types of seizures, showing a lack of pathology using magnetic resonance imaging (MRI) and computed tomography scanning. However, JME is associated with a particular personality profile, and behavioral and neuropsychologic studies have suggested the possible involvement of frontal lobe dysfunction. The development of highly sensitive neuroimaging techniques has provided a means of elucidating the underlying mechanisms of JME. For example, positron emission tomography has demonstrated neurotransmitter changes in the cerebral cortex, quantitative MRI has revealed significant abnormalities of cortical gray matter in medial frontal areas, and 1H-magnetic resonance spectroscopy has shown evidence of thalamic dysfunction, which appears to be progressive. Such techniques provide evidence of multi-focal disease mechanisms, suggesting that JME is a frontal lobe variant of a multi-regional, thalamocortical 'network' epilepsy, rather than a generalized epilepsy syndrome.

Brain Mapping↗
PubMed2006

Sex differences in face recognition memory in patients with temporal lobe epilepsy, patients with generalized epilepsy, and healthy controls.

The influence of sex on face recognition memory was studied in 49 patients with temporal lobe epilepsy, 20 patients with generalized epilepsy, and 32 healthy controls. After learning 20 faces, serially presented for 5 seconds each, subjects had to recognize the 20 among 40 faces (including 20 new faces) immediately and 24 hours later. Women had better face recognition than men, with no significant differences between groups. Women's advantage was due mainly to superior delayed recognition. Taken together, the results suggest that sex has a similar impact on face recognition in patients with epilepsy and healthy controls, and that testing delayed face recognition raises sensitivity for sex differences. The influence of sex on face recognition in patients with epilepsy should be acknowledged when evaluating individuals or comparing groups.

Adult↗
PubMed2005

Symptomatic epilepsies imitating idiopathic generalized epilepsies.

The diagnosis of idiopathic generalized epilepsies (IGEs) is not generally difficult if one follows the clinical and electroencephalogram (EEG) definitions of each subsyndrome that constitutes IGEs. In contrast, symptomatic epilepsies develop based on organic brain lesions and are easily diagnosed by the presence of developmental delay, neurologic abnormalities, and a characteristic seizure and EEG pattern. However, in clinical practice, it is sometimes difficult to differentiate IGEs from symptomatic epilepsies, especially when the clinical course from the onset of epilepsy is too short to exhibit typical clinical and EEG findings of either epilepsy type, or when patients with symptomatic epilepsies have atypical features that imitate the clinical characteristics of IGEs. The neurodegenerative or metabolic disorders at times start during the clinical course with epileptic seizures and later show typical neurologic abnormalities. The newly recognized metabolic disorder of glucose transporter type 1 deficiency syndrome (Glut-1 DS) may start with myoclonic seizures at an age of less than 1 year and imitate benign myoclonic epilepsy in infancy early in the clinical course. Progressive myoclonus epilepsies (PMEs) that develop at 1-4 years of age at times imitate epilepsy with myoclonic-astatic seizures with respect to the presence of astatic seizures and an epileptic encephalopathic EEG pattern. In addition, young children with focal cortical dysplasia may also have similar clinical and EEG patterns, although the latter may become localized after treatment. Approximately 15% of patients with juvenile myoclonic epilepsy (JME) are resistant to antiepileptic drugs (AEDs) and may require extensive study to make a differential diagnosis from symptomatic epilepsies. PMEs that develop during adolescence may imitate JME early in the clinical course; however, a detailed history and the differentiation between myoclonic seizures and myoclonus would help to distinguish both conditions. The diagnosis of IGEs is very demanding for patients with atypical features with regard to seizure type, EEG findings, and response to appropriate AEDs.

Adolescent↗
PubMed2005

Seizures of idiopathic generalized epilepsies.

Idiopathic generalized epilepsies (IGEs) comprise at least 40% of epilepsies in the United States, 20% in Mexico, and 8% in Central America. Here, we review seizure phenotypes across IGE syndromes, their response to treatment and advances in molecular genetics that influence nosology. Our review included the Medline database from 1945 to 2005 and our prospectively collected Genetic Epilepsy Studies (GENESS) Consortium database. Generalized seizures occur with different and similar semiologies, frequencies, and patterns, ages at onset, and outcomes in different IGEs, suggesting common neuroanatomical pathways for seizure phenotypes. However, the same seizure phenotypes respond differently to the same treatments in different IGEs, suggesting different molecular defects across syndromes. De novo mutations in SCN1A in sporadic Dravet syndrome and germline mutations in SCN1A, SCN1B, and SCN2A in generalized epilepsies with febrile seizures plus have unraveled the heterogenous myoclonic epilepsies of infancy and early childhood. Mutations in GABRA1, GABRG2, and GABRB3 are associated with absence seizures, while mutations in CLCN2 and myoclonin/EFHC1 substantiate juvenile myoclonic epilepsy as a clinical entity. Refined understanding of seizure phenotypes, their semiology, frequencies, and patterns together with the identification of molecular lesions in IGEs continue to accelerate the development of molecular epileptology.

Adolescent↗
PubMed2004

Evidence for linkage between juvenile myoclonic epilepsy-related idiopathic generalized epilepsy and 6p11-12 in Dutch families.

PURPOSE: Previous linkage studies provided evidence for juvenile myoclonic epilepsy (JME) susceptibility loci at 6p11-12, HLA-6p21.3 region, 15q14, and 5q34. These results indicate locus heterogeneity or interpopulation differences, thus underlining the importance of replication studies. METHODS: We describe a replication linkage study of the 6p-q13 region in 18 families ascertained from JME probands of Dutch descent. In the presence of heterogeneity, the definition of the disease status may be crucial, and we therefore used two disease phenotypes: narrow [JME/idiopathic generalized epilepsy (IGE)-"only"] and broad (JME/IGE-plus-fast EEG background activity). RESULTS: We found evidence of linkage at 6p11-12 in multipoint analyses (p < 0.01 in a replication study) for both these disease definitions. Analysis of this region, assuming heterogeneity and autosomal dominant inheritance with a conservative 60% of penetrance, gave a maximum multipoint parametric lod score of 2.07 at D6S1573 for the narrow phenotype and peaked at 2.53 between D6S1623 and D6S1573 for the broad phenotype. The p value for nonparametric linkage reached 0.0013 for the narrow phenotype and 0.0010 for the broad. Significant exclusion (lod score <or=2) was found for the HLA region and for 10 to 30 cM telomeric to HLA. Our results provide evidence for a susceptibility locus for JME/IGE-plus-fast EEG background activity at 6p11-12. CONCLUSIONS: Additionally, by using a narrow definition, we were able to confirm previous evidence for a JME-IGE locus at this location.

Adolescent↗
PubMed1995

Mapping of genes predisposing to idiopathic generalized epilepsy.

Idiopathic generalized epilepsy (IGE) is characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Twin and family studies suggest that genetic factors play a key part in IGE. A multilocus model appears to best fit the observed inheritance patterns. Mapping of IGE-related genes has been previously attempted using parametric methods, with conflicting results. In particular, recent evidence argues both for and against a chromosome 6p locus (EJM1) for juvenile myoclonic epilepsy, a subtype of IGE. We have approached the problem of mapping IGE loci using non-parametric methods, which have recently been successful for other complex diseases. No evidence for linkage to chromosome 6p was obtained. However, we obtained evidence for involvement of a locus at chromosome 8q24, close to the marker D8S256. The same 8q24 region was previously implicated in families with benign neonatal familial convulsions (BNFC), a generalized epilepsy syndrome that is inherited as a simple dominant mendelian trait. There is an apparent conserved syntenic group of genes in human 8q24 and a region of mouse chromosome 15, which harbors the stargazer (stg) locus. Homozygous mutant mice at the stg locus show a form of generalized epilepsy that resembles human absence epilepsy. Our findings may have implications for a locus on 8q24 predisposing to IGE.

Chromosome Mapping↗
PubMed1986

Regional cerebral blood flow during interictal state: differences between temporal lobe epilepsy and primary generalized epilepsy.

Regional cerebral blood flow (rCBF) was investigated during interictal state by 133Xenon intravenous clearance technique in two groups of epileptic patients: group I (n = 28) having partial complex seizures (temporal lobe epilepsy); group II (n = 14) having generalized seizures (primary generalized epilepsy). Mean hemispheric CBF was decreased in group I and unchanged in group II compared to normal controls. Modifications in rCBF pattern were observed in group I but not in group II. A marked hypoperfusion of one temporal region was found in patients from group I showing a unilateral and fixed epileptic focus. Hypoperfusion of other cerebral areas at a distance from the epileptic focus was greater for patients with a left epileptic focus than for those with a right epileptic focus. Patients with the same severity of disease and bilateral and variable foci had no significant modification of mean hemispheric CBF and rCBF distribution. These observations indicate that interictal investigations of rCBF may be of interest for a differential classification of epilepsy.

Adolescent↗
PubMed2006

Voxel-based morphometry in patients with idiopathic generalized epilepsies.

Idiopathic generalized epilepsies (IGE) are a group of frequent age-related epilepsy syndromes. IGE are clinically characterized by generalized tonic-clonic, myoclonic and absence seizures. According to predominant seizure type and age of onset, IGE are divided in subsyndromes: childhood absence and juvenile absence epilepsy (AE), juvenile myoclonic epilepsy (JME) and generalized tonic-clonic seizures on awakening (GTCS). The limits between these subsyndromes are not well defined, supporting the existence of only one major syndrome. Visual assessment of routine magnetic resonance imaging (MRI) in patients with IGE is normal. MRI voxel-based morphometry (VBM) uses automatically segmented gray and white matter for comparisons, eliminating the investigator bias. We used VBM to study 120 individuals (47 controls, 44 with JME, 24 with AE and 15 with GTCS) to investigate the presence of subtle structural abnormalities in IGE subsyndromes. VBM was performed searching for abnormalities on gray matter concentration (GMC) between patients groups and controls. Compared to controls, JME presented increased GMC in frontobasal region and AE showed increased GMC in the superior mesiofrontal region. The GTCS group did not differ from controls. There were no areas of reduced GMC with the statistical level selected. Region of interest analysis showed increased GMC in the anterior portion of the thalamus in patients with absence seizures. Our results support subtle GMC abnormalities in patients with JME and AE when compared to controls. These findings suggest the existence of different patterns of cortical abnormalities in IGE subsyndromes.

Adolescent↗
PubMed2000

Mutation screening of the chromosome 8q24.3-human activity-regulated cytoskeleton-associated gene (ARC) in idiopathic generalized epilepsy.

Idiopathic generalized epilepsy (IGE) comprises a heterogeneous group of disorders, in which a high genetic predisposition and a complex mode of inheritance have been suggested. However, genes, which confer liability to common IGE subtypes including juvenile myoclonic epilepsy (JME) and childhood absence epilepsy (CAE) have not been identified so far. Here, we tested the hypothesis that genetic variation in the human homolog of the <<< >>> (ARC) contributes to the etiology of common IGE disorders. The gene has recently been mapped to chromosome 8q24.3, a region which spans previously identified major IGE susceptibility loci. A systematic search for mutations was performed in 143 patients with a known family history of IGE. However, no evidence for functional variants was found in the ARC coding sequence. Nevertheless, we detected a novel common C489T single nucleotide polymorphism, which provides a useful marker in genetic linkage and association studies. By performing a population- and family-based study we however failed to show significant association between this novel single nucleotide polymorphism and IGE, a finding, which most likely rules out that genetic variation in or close to the ARC gene confers liability to common IGE subtypes.

Adult↗
PubMed2000

No evidence for association between the KCNQ3 gene and susceptibility to idiopathic generalized epilepsy.

Idiopathic generalized epilepsy (IGE) comprises a heterogeneous group of disorders, in which a high genetic predisposition and a complex mode of inheritance have been suggested. Recent identification of ion channel gene mutations in Mendelian epileptic disorders suggests genetically driven neuronal hyperexcitability as one important factor in epileptogenesis. Mutations in two neuronal voltage-gated potassium channel genes (KCNQ2 and KCNQ3) have already been shown to cause epilepsy (BFNC), and we now tested the hypothesis that genetic variation in the KCNQ3 gene confers liability to common IGE subtypes. Length variation of two intragenic polymorphic markers (D8S558 and D8S1835) were therefore assessed in 71 nuclear families ascertained for an affected child. However, the transmission-disequilibrium-test did not show significant differences between the transmitted and non-transmitted parental alleles. Thus, our findings do not provide evidence that genetic variation in the KCNQ3 gene exerts a relevant effect in the etiology of common IGE subtypes.

Alleles↗
PubMed2003

Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.

Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder affecting about 0.4% of the world's population. Mutations in ten genes causing distinct forms of idiopathic epilepsy have been identified so far, but the genetic basis of many IGE subtypes is still unknown. Here we report a gene associated with the four most common IGE subtypes: childhood and juvenile absence epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal seizures on awakening (EGMA; ref. 8). We identified three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations result in (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations that provide distinct explanations for their pathogenic phenotypes. M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition. G715E alters voltage-dependent gating, which may cause membrane depolarization and hyperexcitability.

Adolescent↗
PubMed2004

Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy.

Idiopathic generalized epilepsy (IGE) is a class of genetically determined, phenotypically related epilepsy syndromes. Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IGEs. We report a single-nucleotide polymorphism (SNP) association analysis of the region around the marker locus with the high LOD score. This analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme 2 (ME2) is the gene predisposing to IGE. We also observed association among subgroups of IGE syndromes. An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype. Both the linkage analysis and the association analysis support recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. ME2 is a genome-coded mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). The results suggest that GABA synthesis disruption predisposes to common IGE and that clinical seizures are triggered when mutations at other genes, or perhaps other insults, are present.

Adolescent↗
PubMed2005

The management of idiopathic generalized epilepsies.

Idiopathic generalized epilepsies (IGEs) are a well defined group of epilepsies, with onset predominantly in childhood. Recent evidence suggests that IGEs may also be prevalent but under-diagnosed in adults. IGEs respond well to appropriate treatment and 80-90% of cases become fully controlled. However, correct identification of IGE and selection of a broad-spectrum antiepileptic drug (AED) is crucial if cases of 'pseudo-intractability' are to be avoided. Preliminary evidence suggests that some of the newer AEDs are broad spectrum and may offer advantages in the treatment of IGEs. There is strong evidence that childhood-, adolescent- and adult-onset IGEs share biologic determinants and are best viewed as a spectrum or continuum of conditions. The diagnosis of IGE, even as a group, is very important for proper management.

Adolescent↗