[Generalized epilepsy induced by trazodone].
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Effect of vagus nerve stimulation on adults with pharmacoresistant generalized epilepsy syndromes.
INTRODUCTION: Although vagus nerve stimulation (VNS) therapy is approved for the treatment of partial onset seizures, its efficacy for generalized seizures has not been fully evaluated. This Investigational Device Exemption assessed the outcome of VNS therapy among patients with generalized epilepsy syndromes. METHODS: Sixteen patients with pharmacoresistant generalized epilepsy syndromes and stable antiepileptic drug (AED) regimens were implanted with the VNS therapy device and were evaluated for changes in seizure frequency and type between baseline and follow-up of 12-21 months. RESULTS: The patients experienced a statistically significant overall median seizure frequency reduction of 43.3% (P = 0.002, Wilcoxon signed rank test) after 12-21 months of VNS therapy. Types of seizures that may involve a fall or collapse decreased with reductions in the frequency of myoclonic (60% reduction, n = 9; P = 0.016, Wilcoxon signed rank test), tonic (75% reduction, n = 8, NS), atonic (98.6%, n = 3, NS), and clonic seizures (86.7%, n = 1, NS). CONCLUSION: The benefits of reduced seizure frequency and reduced risk of injury merit consideration of VNS therapy for patients with pharmacoresistant generalized seizure syndromes.
Adult↗
Use and abuse of EEG in the diagnosis of idiopathic generalized epilepsies.
This article concentrates on the role of electroencephalograms (EEGs) in the diagnosis and management of patients with idiopathic generalized epilepsies (IGEs). We review the morphologic and behavioral characteristics of the interictal and ictal EEG markers of IGE that should guide recording strategies to augment its diagnostic yield, and we attempt to delineate those particular features that may be relevant to different IGE syndromes. We also explore the electrographic boundaries between IGEs and cryptogenic/symptomatic generalized and focal epilepsies, and focal/secondary generalized epilepsies, with particular relevance to the phenomena of focal abnormalities and secondary bilateral synchrony, commenting on possible diagnostic pitfalls and areas of uncertainty.
Biomarkers↗
Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus.
Recent findings from studies of two families have shown that mutations in the GABA(A)-receptor gamma2 subunit are associated with generalized epilepsies and febrile seizures. Here we describe a family that has generalized epilepsy with febrile seizures plus (GEFS(+)), including an individual with severe myoclonic epilepsy of infancy, in whom a third GABA(A)-receptor gamma2-subunit mutation was found. This mutation lies in the intracellular loop between the third and fourth transmembrane domains of the GABA(A)-receptor gamma2 subunit and introduces a premature stop codon at Q351 in the mature protein. GABA sensitivity in Xenopus laevis oocytes expressing the mutant gamma2(Q351X) subunit is completely abolished, and fluorescent-microscopy studies have shown that receptors containing GFP-labeled gamma2(Q351X) protein are retained in the lumen of the endoplasmic reticulum. This finding reinforces the involvement of GABA(A) receptors in epilepsy.
Animals↗
Association of the 867Asp variant of the human anion exchanger 3 gene with common subtypes of idiopathic generalized epilepsy.
Genetic factors play a major role in the etiology of idiopathic generalized epilepsies (IGE). Our recent genome-wide search revealed suggestive evidence for a susceptibility locus for common IGE syndromes in the chromosomal region 2q36. The gene encoding the anion exchanger isoform 3 (AE3; gene symbol: SLC4A3) has been mapped to this candidate region. AE3 is prominently expressed in the brain and performs an electroneutral exchange of chloride and bicarbonate. To study the potential role of AE3 in the epileptogenesis of IGE, we performed a mutation analysis of the AE3 coding region, including the adjacent exon/intron boundaries, and the 5'-untranslated region in 16 IGE probands of families linked to chromosome 2q36 (cumulative two-point lod score: Z=5.32 at D2S371). Three exonic sequence variants were found: exon 17: 2600C/A, Ala867Asp; exon 21: 3391C/T, Leu1131Leu; exon 23: 3771G/A, 3'-UTR. Our subsequent population-based association study of the Ala867Asp substitution polymorphism revealed a significant increase of the 867Asp variant in 366 unrelated German IGE patients compared with 183 German control subjects (chi(2)=5.37, df=1, P=0.021). Consistently, the transmission disequilibrium test (TDT) of 121 parent-child trios showed a significant preferential transmission of the 867Asp allele (McNemar chi(2)=5.81, df=1, P=0.016). Our results support the hypothesis that variation of the AE3 gene confers a common but small susceptibility effect to the etiology of a broad spectrum of IGE syndromes.
Alleles↗
Refinement of map position of the human GluR6 kainate receptor gene (GRIK2) and lack of association and linkage with idiopathic generalized epilepsies.
Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The pivotal function of glutamate receptors (GluRs) in excitatory neurotransmission implicates their involvement in epileptogenesis and genetic susceptibility to IGEs. A trinucleotide repeat polymorphism detected in the 3' untranslated region of the kainate-selective GluR6 receptor gene (GRIK2) on chromosome 6 makes it possible to perform linkage and association studies with this high-ranking candidate gene. The present study tested the hypothesis that allelic variants of GRIK2 contribute to the genetic susceptibility to the common IGEs. Linkage and association analyses were conducted in 63 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, or childhood absence epilepsy. Our linkage and association results suggest that allelic variants of GRIK2 are not involved in the expression of the common familial IGEs, and radiation hybrid mapping assigns GRIK2 to the chromosomal region 6q16.3-q21. This localization excludes GRIK2 as a candidate for the putative IGE susceptibility locus "EJM1" on the short arm of chromosome 6.
Chromosome Mapping↗
Generalized epilepsy with febrile seizures plus (GEFS+): clinical spectrum in seven Italian families unrelated to SCN1A, SCN1B, and GABRG2 gene mutations.
PURPOSE: We describe seven Italian families with generalized epilepsy with febrile seizures plus (GEFS+), in which mutations of SCN1A, SCN1B, and GABRG2 genes were excluded and compare their clinical spectrum with that of previously reported GEFS+ with known mutations. METHODS: We performed a clinical study of seven families (167 individuals). The molecular study included analysis of polymerase chain reaction (PCR) fragments of SCN1A and SCN1B exons by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing of GABRG2 in all families. We excluded SCN1A, SCN1B, and GABRG2 genes with linkage analysis in a large pedigree and directly sequenced SCN2A in a family with neonatal-infantile seizures onset. We compared the epilepsy phenotypes observed in our families with those of GEFS+ families harboring mutations of SCN1A, SCN1B, and GABRG2 and estimated the percentage of mutations of these genes among GEFS+ cases by reviewing all published studies. RESULTS: Inheritance was autosomal dominant with 69% penetrance. Forty-one individuals had epilepsy: 29 had a phenotype consistent with GEFS+; seven had idiopathic generalized epilepsy (IGE); in three, the epilepsy type could not be classified; and two were considered phenocopies. Clinical phenotypes included FS+ (29.2%), FS (29.2%), IGE (18.2%), FS+ with focal seizures (13%) or absence seizures (2.6%), and FS with absence seizures (2.6%). Molecular study of SCN1A, SCN2A, SCN1B, and GABRG2 did not reveal any mutation. Results of our study and literature review indicate that mutations of SCN1A, SCN2A, SCN1B, and GABRG2 in patients with GEFS+ are rare. CONCLUSIONS: The most frequently observed phenotypes matched those reported in families with mutations of the SCN1A, SCN1B, and GABRG2 genes. IGE and GEFS+ may overlap in some families, suggesting a shared genetic mechanism. The observation that 13% of affected individuals had focal epilepsy confirms previously reported rates and should prompt a reformulation of the "GEFS+" concept to include focal epileptogenesis.
Adolescent↗
[Combined therapy with lamotrigine++ in primary generalized epilepsy in adult patients].
An attempt is presented to use Lamictal (lamotrigine) produced by GlaxoWellcome in 30 patients with primary generalized epilepsy, already taking one of antiepileptic drugs, but refractory to this treatment. The patients were treated with carbamazepine (Amizepin) 600-1200 mg daily or with sodium valproate (Depakine) 1200-1600 mg daily. In the course of add-on therapy patients were receiving in first 4 weeks increasing doses of Lamictal starting from 50 mg or 25 mg (patients treated with sodium valproate). Maintenance dose of lamotrigine was 200 mg daily in two divided doses. The results of first three months of the treatment were generally positive. Half the patients experienced a reduction in seizure count by more than a half, what testify the Lamictal is a valuable medication in the treatment of primary generalized epilepsy. The observed side effects had transitory character.
Adult↗
Idiopathic generalized epilepsies: clinical and electroencephalogram diagnosis and treatment.
This review concentrates on the principles of the clinical and electroencephalogram diagnosis of idiopathic generalized epilepsies and their treatment. The electroclinical variability of the main seizure types is detailed and particular emphasis is placed on the differential diagnosis from other seizures and nonepileptic conditions that is essential for the optimal management of these patients. The authors review the various idiopathic generalized epilepsy subsyndromes and conditions that are included in both the 1989 International League Against Epilepsy classification system and the recently proposed International League Against Epilepsy scheme, but also syndromes and forms that have not been formally recognized. Finally, the authors describe the principles of antiepileptic drug treatment with the old and newer drugs, and their specific indications and contraindications in the various syndromes and seizure types.
Anticonvulsants↗
Sleep architecture in children with idiopathic generalized epilepsy.
PURPOSE: Children with epilepsy experience sleep disturbances, behavioral and attentional problems at higher rates than their peers. However, the relation between sleep disturbances and the observed behavioral and attentional abnormalities is poorly defined. METHODS: Children with primary generalized epilepsy who were seizure free and between the ages of 5 and 18 years were matched with age- and gender-matched healthy controls and underwent two consecutive nights of nocturnal polysomnography with extended electroencephalography. Connor's Continuous Performance Test (CPT) was administered to assess daytime attentional function. Parents completed the Child Behavior Checklist (CBCL) to assess their emotional-behavioral status. Two sample t tests were used to examine group differences. Spearman correlations were used to examine the relation between sleep variables and behavior and attention variables. Multiple regression analysis was used to identify independent predictors of abnormal behavior and attention among patients. RESULTS: Eleven children with primary generalized epilepsy and eight age- and sex-matched controls participated in the study. Children with epilepsy had longer stage 1 sleep percentage (7.19 +/- 3.2 vs. 4.8 +/- 3.5; p = 0.05) and latency to rapid-eye-movement (REM) sleep (123.5 +/- 40.1 vs. 101.75 +/- 24.3; p = 0.018) compared with controls. Children with epilepsy had worse attention (CPT index, 10.94 +/- 6.55 vs. 3.42 +/- 4.04; p = 0.004) and exhibited significantly higher CBCL Total Behavior and Internalizing Behavior Problem scales. Whereas regression analysis showed no independent predictors of abnormal behavior and attention, a tendency toward association between CBCL total behavior scale and REM percentage (r= 0.55; p = 0.07), and between CPT overall index and stage 1 sleep percentage (r= 0.40; p = 0.10) was noted. CONCLUSIONS: Sleep architecture is abnormal in children with primary generalized epilepsy. Further studies are needed to determine whether abnormalities in sleep architecture contribute to poor daytime behavior and attention.
Adolescent↗
Genetic architecture of idiopathic generalized epilepsy: clinical genetic analysis of 55 multiplex families.
PURPOSE: In families with idiopathic generalized epilepsy (IGE), multiple IGE subsyndromes may occur. We performed a genetic study of IGE families to clarify the genetic relation of the IGE subsyndromes and to improve understanding of the mode(s) of inheritance. METHODS: Clinical and genealogic data were obtained on probands with IGE and family members with a history of seizures. Families were grouped according to the probands' IGE subsyndrome: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with tonic-clonic seizures only (IGE-TCS). The subsyndromes in the relatives were analyzed. Mutations in genes encoding alpha1 and gamma 2 gamma-aminobutyric acid (GABA)-receptor subunits, alpha1 and beta1 sodium channel subunits, and the chloride channel CLC-2 were sought. RESULTS: Fifty-five families were studied. 122 (13%) of 937 first- and second-degree relatives had seizures. Phenotypic concordance within families of CAE and JME probands was 28 and 27%, respectively. JAE and IGE-TCS families had a much lower concordance (10 and 13%), and in the JAE group, 31% of relatives had CAE. JME was rare among affected relatives of CAE and JAE probands and vice versa. Mothers were more frequently affected than fathers. No GABA-receptor or sodium or chloride channel gene mutations were identified. CONCLUSIONS: The clinical genetic analysis of this set of families suggests that CAE and JAE share a close genetic relation, whereas JME is a more distinct entity. Febrile seizures and epilepsy with unclassified tonic-clonic seizures were frequent in affected relatives of all IGE individuals, perhaps representing a nonspecific susceptibility to seizures. A maternal effect also was seen. Our findings are consistent with an oligogenic model of inheritance.
Adolescent↗
Auditory event related potentials relate with the clinical progression in idiopathic generalized epilepsy.
Auditory event related potential (ERP) was studied in 60 patients with idiopathic generalized epilepsy and 33 age and sex matched healthy subjects. Thirty nine patients came to the control three months later and were reassessed. All auditory evoked potential latencies were prolonged in epileptics compared to those of healthy subjects. Multiple drug using or history of more than 100 seizures was associated with prolonged P3 latency. History of status epilepticus was observed together with prolongation of N2 and P3 latencies. Patients using their antiepileptic drugs more properly after the first control showed shortened P3 latency in the second control.
Adult↗
Neuron density in the molecular layer of the frontal cortex in primary generalized epilepsy.
Developmental disturbance of the brain as a factor in the causation of epilepsies has been suspected for a long time. An increase of nerve cells in the stratum moleculare, which is qualitatively observed in primary generalized epilepsy, is thought to be an indicator for slight maldevelopment. In this morphometric study, the neuron density of layer I in the frontal lobe in primary generalized epilepsy is measured. Compared with age-matched controls, the neuron density in primary generalized epilepsy is significantly increased. Thus, neuron density could be a significant index for the disturbance of regional maturation of the cortex.
Adolescent↗
[A course of idiopathic generalized epilepsy in adult and elderly patients].
Thirty-six patients with idiopathic generalized epilepsy (IGE) aged 35-67 years (mean age 44.4 +/- 10.6 years, 14 male, 22 female) have been studied. Ten of them were over 50 years, 8 had a diagnosis of juvenile absence epilepsy (JAE); 12--juvenile myoclonic epilepsy (JME) and 16--awakening epilepsy (AE), IGE with isolated generalized tonic-clonic seizures. The control group included 80 patients with IGE (22 male, 58 female aged 15-34 years, mean age 20.5 +/- 4.3 years), 29 of them being affected with JAE, 28--JME, 23--AE. Elderly patients with IGE experienced difficulties in the control over absences, myoclonic seizures and generalized seizures. In this group, the seizures-free cases were rare. The results suggest worse clinical prognosis of IGE for elderly patients as compared with young ones.
Adolescent↗
A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy.
We recently described mutations of the neuronal sodium-channel alpha-subunit gene, SCN1A, on chromosome 2q24 in two families with generalized epilepsy with febrile seizures plus (GEFS+) type 2. To assess the contribution that SCN1A makes to other types of epilepsy, 226 patients with either juvenile myoclonic epilepsy, absence epilepsy, or febrile convulsions were screened by conformation-sensitive gel electrophoresis and manual sequencing of variants; the sample included 165 probands from multiplex families and 61 sporadic cases. The novel mutation W1204R was identified in a family with GEFS+. Seven other coding changes were observed; three of these are potential disease-causing mutations. Two common haplotypes, with frequencies of .67 and .33, were defined by five single-nucleotide polymorphisms (SNPs) spanning a 14-kb region of linkage disequilibrium. An SNP located 18 bp upstream of the splice-acceptor site for exon 3 was observed in 7 of the 226 patients but was not present in 185 controls, suggesting possible association with a disease mutation. This work has confirmed the role of SCN1A in GEFS+, by identification of a novel mutation in a previously undescribed family. Although a few candidate disease alleles were identified, the patient survey suggests that SCN1A is not a major contributor to idiopathic generalized epilepsy. The SCN1A haplotypes and SNPs identified here will be useful in future association and linkage studies.
Amino Acid Sequence↗
The genetics of idiopathic generalized epilepsy: implications for the understanding of its aetiology.
Epilepsy is one of the most common neurological disorders. Both inherited and acquired factors contribute to its multifactorial pathogenesis. A genetic predisposition plays a major role in the aetiology of the common idiopathic generalized epilepsies. Susceptibility genes for two syndromes of idiopathic generalized epilepsies, the benign familial neonatal convulsions and juvenile myoclonic epilepsy, have been assigned to the chromosomal regions 20q13 (EBN1), 8q24 (EBN2) and 6p21 (EJM1). Positional cloning of the mutations causing these traits will help to elucidate the molecular pathways of epileptogenesis and will imply a classification on a neurobiological basis. Insights into the underlying impairment of neuronal excitability should provide new concepts for the development of rational treatment strategies.
Animals↗
Models of primary generalized epilepsy.
The most important recent development in primary generalized epilepsy has been the use of in-vitro and in-vivo models to delineate the neuronal populations and intrinsic mechanisms, which generate the synchronized thalamocortical burst-firing of absence seizures. Candidate molecular mechanisms, which may be critically involved in the pathogenesis of absence seizures in selected animal models, include the following: altered biophysical properties of T-type calcium channels in the genetic absence epilepsy rat of Strasbourg (GAERS) model; increased numbers of gamma-aminobutyric acid, B subtype receptors in the lethargic mouse (lh/lh mouse) model; and changes in the subunit composition of gamma-aminobutyric acid, A subtype receptors in the GAERS model. Regarding generalized convulsive seizures, neuronal populations within the inferior and superior colliculi appear to regulate seizures in the genetic epilepsy-prone rat (GEPR) model, and subpopulations within the substantia nigra pars reticulata (SNR) appear to regulate seizures in the fluorothyl model. Deficiencies in the function of GABAergic and noradrenergic receptors may underlie generalized convulsive seizures in the GEPR model.
Animals↗
Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations.
We sequenced 61 patients with various idiopathic generalized epilepsy (IGE) syndromes for mutations in the EFHC1 gene. We detected three novel heterozygous missense mutations (I174V, C259Y, A394S) and one possibly pathogenic variant in the 3' UTR (2014t>c). The mutation I174V was also detected in 1 of 372 screened patients with temporal lobe epilepsy. We conclude that mutations in the EFHC1 gene may underlie different types of epilepsy syndromes.
3' Untranslated Regions↗