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Results for “Epilepsy, Generalized”

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PubMed1999

[Limitations of the concept of idiopathic generalized epilepsy].

The 1989 International Classification of Epilepsies confirmed the existence of a category of Idiopathic Generalized Epilepsies (IGE), which includes a list of age-dependent syndromes that are supposed to share a common mechanism. Recent clinical, experimental and genetic data have shown that the group of IGEs is indeed heterogeneous, that various mechanisms are implied, and that the limits of this category remain comparatively unclear, especially versus cryptogenic or symptomatic generalized epilepsies. There is no such thing as a truly "generalized" epilepsy, and "idiopathic" means in fact that epileptic seizures are the only, or predominant symptom of the condition. The pharmacological sensitivity (some drugs control IGEs, other drugs usually aggravate them) seems to be common to a majority of the syndromes of IGE. The concept of IGE remains useful in clinical practice, and should be widened to include newly described syndromes.

Age Factors↗

PubMed2002

Functional and biochemical analysis of a sodium channel beta1 subunit mutation responsible for generalized epilepsy with febrile seizures plus type 1.

Generalized epilepsy with febrile seizures plus type 1 is an inherited human epileptic syndrome, associated with a cysteine-to-tryptophan (C121W) mutation in the extracellular immunoglobin domain of the auxiliary beta1 subunit of the voltage-gated sodium channel. The mutation disrupts beta1 function, but how this leads to epilepsy is not understood. In this study, we make several observations that may be relevant for understanding why this beta1 mutation results in seizures. First, using electrophysiological recordings from mammalian cell lines, coexpressing sodium channel alpha subunits and either wild-type beta1 or C121Wbeta1, we show that loss of beta1 functional modulation, caused by the C121W mutation, leads to increased sodium channel availability at hyperpolarized membrane potentials and reduced sodium channel rundown during high-frequency channel activity, compared with channels coexpressed with wild-type beta1. In contrast, neither wild-type beta1 nor C121Wbeta1 significantly affected sodium current time course or the voltage dependence of channel activation. We also show, using a Drosophila S2 cell adhesion assay, that the C121W mutation disrupts beta1-beta1 homophilic cell adhesion, suggesting that the mutation may alter the ability of beta1 to mediate protein-protein interactions critical for sodium channel localization. Finally, we demonstrate that neither functional modulation nor cell adhesion mediated by wild-type beta1 is occluded by coexpression of C121Wbeta1, arguing against the idea that the mutant beta1 acts as a dominant-negative subunit. Together, these data suggest that C121Wbeta1 causes subtle effects on channel function and subcellular distribution that bias neurons toward hyperexcitabity and epileptogenesis.

Animals↗

PubMed1998

[Anticonvulsants can aggravate idiopathic generalized epilepsy].

Antiepileptic drugs can sometimes worsen idiopathic generalized epilepsies. Relevant data are based on empirical experience of epileptologists and on few published case-reports according to the suspected drug with serious methodological limitations. Some animal models of epileptic syndromes such as genetic models of absence seizures in rat seem to be helpful for understanding the possible mechanisms underlying drug-induced syndrome aggravation. Adequate epileptic syndrome diagnosis is needed before starting antiepileptic drug.

Animals↗

PubMed2000

A new locus for generalized epilepsy with febrile seizures plus maps to chromosome 2.

Generalized epilepsy with febrile seizures plus (GEFS+) is a recently recognized but relatively common form of inherited childhood-onset epilepsy with heterogeneous epilepsy phenotypes. We genotyped 41 family members, including 21 affected individuals, to localize the gene causing epilepsy in a large family segregating an autosomal dominant form of GEFS+. A genomewide search examining 197 markers identified linkage of GEFS+ to chromosome 2, on the basis of an initial positive LOD score for marker D2S294 (Z=4.4, recombination fraction [straight theta] = 0). A total of 24 markers were tested on chromosome 2q, to define the smallest candidate region for GEFS+. The highest two-point LOD score (Zmax=5.29; straight theta=0) was obtained with marker D2S324. Critical recombination events mapped the GEFS+ gene to a 29-cM region flanked by markers D2S156 and D2S311, with the idiopathic generalized epilepsy locus thereby assigned to chromosome 2q23-q31. The existence of the heterogeneous epilepsy phenotypes in this kindred suggests that seizure predisposition determined by the GEFS+ gene on chromosome 2q could be modified by other genes and/or by environmental factors, to produce the different seizure types observed.

Age of Onset↗

PubMed2006

A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies.

Highly alternatively spliced genes may provide complex targets for disease mutations. Structural changes created by missense mutations may differentially affect the activity of alternative gene products, whereas missense, silent and non-coding mutations may alter developmental regulation of splice variant expression. CACNA1H is a human gene encoding Ca(v)3.2 low-voltage-activated, T-type calcium channels associated with bursting behavior in neurons and has been linked to more than 30 mutations apparently predisposing to childhood absence epilepsy (CAE) and other idiopathic generalized epilepsies (IGEs). Biophysical properties, including the effects of missense mutations, have been evaluated previously for a single splice form of Ca(v)3.2 expressed in transformed cell lines. We here show that CACNA1H is alternatively spliced at 12-14 sites, capable of generating both functional and non-functional transcripts. Variable cytoplasmic and extracellular protein domains point to likely differences in gating behavior, sensitivity to neuromodulation and interactions with extracellular matrix. Biophysical profiles of selected physiological Ca(v)3.2 forms reveal variations in kinetics and steady-state gating parameters, most likely to affect membrane firing. These were comparable to or larger than changes reported for previously studied mutations. Missense CAE and IGE mutations were clustered near segments associated with anomalous splicing. Missense and silent mutations were found to destroy, create or change the regulatory specificity of predicted exonic splicing enhancer sequences that may control splicing regulation. We discuss a paradigm for CACNA1H expression of Ca(v)3.2 subunits, which may influence future basic and clinical studies.

Alternative Splicing↗

PubMed2006

Idiopathic generalized epilepsies of adolescence.

The prevalence of idiopathic generalized epilepsies (IGEs) has been assessed as being 15-20% of all epilepsies. The seizure types in IGEs are typical absences, myoclonic jerks, and generalized tonic-clonic seizures (TCS), alone or in varying combinations and with variable severity. The seizures tend to be more frequent on awakening and with sleep deprivation. This group of clinical conditions includes among others, age-related epilepsy syndromes of adolescence such as juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with generalized TCS or epilepsy with grand mal on awakening (EGMA). The classification of IGEs follows two schools of thought; one maintains that IGEs are a group of different and separate syndromes while the other suggests that IGEs are one biological continuum. Patients with IGEs may have mild impairment of cognitive functions, especially verbal memory and other frontal lobe functions, despite a normal IQ, and some seem to have characteristic personality traits, although further studies are needed to support this theory. They appear to lack a degree of self-control, to neglect their physical needs, and are poorly compliant with therapy. Some patients become obstinate and are impressionable. The cognitive and behavioral aspects of these patients suggest an involvement of frontal lobes.

Adolescent↗

PubMed1999

Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome.

We examined the phenotypic variation and clinical genetics in nine families with generalized epilepsy with febrile seizures plus (GEFS+). This genetic epilepsy syndrome with heterogeneous phenotypes was hitherto described in only one family. We obtained genealogical information on 799 individuals and conducted detailed evaluation of 272 individuals. Ninety-one individuals had a history of seizures and 63 had epilepsy consistent with the GEFS+ syndrome. Epilepsy phenotypes were febrile seizures (FS) in 31, febrile seizures plus (FS+) in 15, FS+ with other seizure types (atonic, myoclonic, absence, or complex partial) in 8, and myoclonic-astatic epilepsy in 9 individuals. Inheritance was autosomal dominant with approximately 60% penetrance. This study confirms and expands the spectrum of GEFS+ and provides new insights into the phenotypic relationships and genetics of FS and the generalized epilepsies of childhood. Moreover, the ability to identify large families with this newly recognized common, childhood-onset, generalized genetic epilepsy syndrome suggests that it should be a prime target for attempts to identify genes relevant to FS and generalized epilepsy.

Adult↗

PubMed1993

So-called generalized epilepsy in children leading to frontal epilepsy with a frontal syndrome in adulthood: a clinical, EEG and radiological study of 10 cases.

The authors report 10 cases of epileptic patients with the onset in childhood of the clinical and EEG features of cryptogenic generalized epilepsy which evolved into frontal epilepsy, confirmed by the clinical and EEG features and was associated with a frontal syndrome. CT-scan and MRI showed mild atrophy in the frontal area, while SPECT showed a decrease in the frontal blood flow in 70% of the cases. The authors consider that frontal epilepsy may mimic generalized epilepsy.

Adolescent↗

PubMed2003

[The use of depakene and depakene-chrono in idiopathic generalized epilepsy].

During 5 years, 104 patients with different types of idiopathic generalized epilepsy were treated with depakine and depakine-chrono in monotherapy and polytherapy schedule. Thirty-three patients had childhood absence epilepsy, 34--juvenile absence epilepsy, 33--juvenile myoclonic epilepsy and 3--generalized convulsive seizures in wake up periods. Mean medication dose was 1200 mg daily. Significant improvement of the patient's state was revealed in 50% of the cases, being most efficient in patients with juvenile myoclonic epilepsy (60.6%) and in children absence epilepsy (57.5%). Indices of remission formation and quality changed in the same direction--complete remissions were more frequent in juvenile absence epilepsy. Depakine is concluded to be an effective medication for the treatment of idiopathic generalized epilepsy.

Adolescent↗

PubMed2003

Mental tasks induce gamma EEG with reduced responsiveness in primary generalized epilepsies.

PURPOSE: We previously revealed an interictal increase in intensity of EEG rhythms during quiescent mental activity in the 30- to 100-Hz frequency (gamma) range in primary generalized epilepsy (PGE). We have evidence that there is induction of gamma EEG in normal subjects in response to controlled mental activity. Here we test whether mental tasks further augment interictal gamma oscillations in people with PGE. METHODS: We recorded interictal EEG from patients with PGE and partial epilepsy and compared EEG power spectral responses (increases over resting) during mental tasks. RESULTS: In partial epilepsy, mental tasks (except for alternating checkerboard visual stimulation) induced 1.5- to 2.5-fold increases in power of gamma EEG. In generalized epilepsy, generalized increases of 1.5-fold in gamma EEG were induced by only two mental tasks (reading and subtraction), and enhancement of 1- to 1.5-fold in the remaining six (checkerboard, expectancy, music, learning, recalling, and a video). CONCLUSIONS: Gamma EEG is less responsive to mental activation in PGE than in partial epilepsy, confirming an abnormality in gamma mechanisms in PGE. Our findings also provide a possible mechanistic link between mental activity and seizures in reading- and arithmetic-induced seizures.

Adult↗

PubMed1993

The MEG in evaluation of generalized epilepsy.

This review looks at the magnetoencephalogram (MEG) studies on generalized epilepsy starting from the first cases investigated up to the most recent contributions regarding the photoconvulsive response and the results obtained applying the template analysis. As far as the spike-and-wave complex is concerned, in the cases both of photoconvulsive response and of non-generalized epilepsy, a primary multiregional participation of the cerebral cortex is shown, which, variable in time and often with a side prevalence, is alternated by bisynchronous epileptiform activity starting from midline structures.

Epilepsy, Generalized↗

PubMed1992

Evidence for multiple gene loci in the expression of the common generalized epilepsies.

Our knowledge of genetic factors influencing expression of epilepsy has increased enormously in the last 10 years. In this article, we review the advantages and problems of population genetics studies, twin studies, and linkage analysis as applied to the study of epilepsy. Population genetics, twin studies, and linkage analysis have placed the evidence for the genetic basis of the generalized epilepsies on a firm foundation. The identification and confirmation of a gene locus involved in the expression of juvenile myoclonic epilepsy and other forms of generalized epilepsy is proof of at least one genetic influence. We also review the evidence that other, still-undiscovered genetic factors might influence the expression of other forms of generalized epilepsy.

Brain↗

PubMed2004

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.

Acute Disease↗

PubMed2002

Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B.

Generalized epilepsy with febrile seizures plus (GEFS(+)) is an important childhood genetic epilepsy syndrome with heterogeneous phenotypes, including febrile seizures (FS) and generalized epilepsies of variable severity. Forty unrelated GEFS(+) and FS patients were screened for mutations in the sodium channel beta-subunits SCN1B and SCN2B, and the second GEFS(+) family with an SCN1B mutation is described here. The family had 19 affected individuals: 16 with typical GEFS(+) phenotypes and three with other epilepsy phenotypes. Site-specific mutation within SCN1B remains a rare cause of GEFS(+), and the authors found no evidence to implicate SCN2B in this syndrome.

Amino Acid Substitution↗

PubMed2002

Clinical and genetic analysis of a new multigenerational pedigree with GEFS+ (Generalized Epilepsy with Febrile Seizures Plus).

Febrile seizures affect 2-5% of all children younger than 6 years. A small proportion of children with febrile seizures later develop epilepsy. The syndrome of generalized epilepsy with febrile seizures plus (GEFS+) is a heterogeneous disorder characterized by febrile seizures that may persist beyond age 6 years and nonfebrile seizures. Several genes have been localized for FS by linkage analysis, and three GEFS+ genes (SCN1A, SCN1B, GABRG2) have been identified. We identified a large multigenerational family with GEFS+ in France. All affected members had FSs. Among them, seven had other types of epileptic seizures including FSs after age 6 years, nonfebrile generalized seizures, or partial seizures later in life. Genetic linkage study excluded the candidate genes and loci for FS and GEFS+, thus proving the existence of a new GEFS+ genetic locus underlying the phenotype observed in this family.

Adolescent↗

PubMed1998

[A review of idiopathic generalized epilepsies: absence epilepsy].

We studied the clinical characteristics observed at diagnosis of the initial seizure in different types of epilepsy, particularly in idiopathic generalized epilepsy (IGE), and evaluated the importance of these in the classification of syndromes. The present study analyzes only those IGE initiated by absences leaving the cases initiated by GTC or myoclonic onset for a successive report. We observed differences between cases initiated by absences, those presenting simultaneously with absences and TCG, and those where TCG preceded the absences. Prognosis and evolution are considerably more favourable in cases initiated by absences than in cases with onset preceded by, or simultaneously with, other types of seizures. Besides this difference regarding evolution, it should also be emphasized that the form initiated by absences are more frequent in females, are generally pycnoleptic, appear more often in childhood with a second more moderate peak between 10 and 11 years of age, present more typical clinical-EEG characteristics, and the presence of previous febrile seizures is more notable.

Adolescent↗

PubMed2005

Evidence-based treatment of idiopathic generalized epilepsies with older antiepileptic drugs.

Older antiepileptic drugs continue to play a major role in the treatment of the idiopathic generalized epilepsies. Comparative studies of ethosuximide and valproate have demonstrated equivalence in the treatment of childhood absence epilepsy. Valproate can be regarded as the recommended first-line treatment for juvenile myoclonic epilepsy based on case series reports. Studies in patients with generalized tonic-clonic seizures have not separated out idiopathic from secondary generalized events. Treatment for the other idiopathic generalized epilepsy syndromes lacks evidence other than a few case reports and diverse expert opinion. Further randomized controlled trials of older antiepileptic drugs are recommended to solidify the evidence-based treatment of the idiopathic generalized epilepsies.

Anticonvulsants↗

PubMed2000

Idiopathic generalized epilepsy: lack of significant microdysgenesis.

BACKGROUND: The idiopathic generalized epilepsies (IGE) are classically regarded as due to a functional abnormality. However, microscopic microdysgenetic changes have been reported in the majority of cases by one group. OBJECTIVE: To independently evaluate the microscopic microdysgenetic changes in a controlled, blinded study. METHODS: Five brains with IGE and five age-matched control brains were collected. Blocks were taken from nine standardized Brodmann areas, both hippocampi, and cerebellum. Slides were examined independently by two neuropathologists blinded to patient group, who qualitatively scored microdysgenetic features on standardized data sheets. The results were compared and any discrepancies were rescored by the pathologists together using a double-header microscope. Quantitative neuronal profile counts in the molecular layer in standardized Brodmann areas of frontal cortex and in deep frontal white matter were performed. RESULTS: Microdysgenetic features in nine Brodmann areas, hippocampi, and cerebellum were not increased in brains from subjects with IGE compared with control brains. Quantitative neuronal profile counts in the molecular layer of frontal cortex and deep frontal white matter were not increased in IGE compared with controls. CONCLUSIONS: This controlled, blinded study did not replicate the results of previous reports of microdysgenesis in IGE. Although factors such as syndrome heterogeneity and sample size may explain the discrepancy, technical factors could also play a role. The current ion channel hypothesis for the pathogenesis of IGE does not preclude microscopic or ultramicroscopic abnormalities and the search for these should continue.

Adult↗