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Results for “Epilepsy, Generalized”

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At least 613 records · Page 34Linked to original sources

PubMed2005

An epilepsy mutation in the beta1 subunit of the voltage-gated sodium channel results in reduced channel sensitivity to phenytoin.

The antiepileptic drug phenytoin inhibits voltage-gated sodium channels. Phenytoin block is enhanced at depolarized membrane potentials and during high frequency channel activation. These properties, which are important for the clinical efficacy of the drug, depend on voltage-dependent channel gating. In this study, we examined the action of phenytoin on sodium channels, comprising a mutant auxiliary beta1 subunit (mutation C121Wbeta1), which causes the inherited epilepsy syndrome, generalized epilepsy with febrile seizures plus (GEFS+). Whole cell sodium currents in Chinese hamster ovary (CHO) cells coexpressing human Na(v)1.3 sodium channels and C121Wbeta1 exhibited altered gating properties, compared to currents in cells coexpressing Na(v)1.3 and wild type beta1. In addition mutant channels were less sensitive to inhibition by phenytoin, showing reduced tonic block at -70mV (EC(50)=26microM for C121Wbeta1 versus 11microM for wild type beta1) and less frequency-dependent inhibition in response to a 20Hz pulse train ( approximately 40% inhibition for C121Wbeta1 versus approximately 70% inhibition for wild type beta1, with 50microM phenytoin). Mutant and wild type channels did not differ in inactivated state affinity for phenytoin, suggesting that their pharmacological differences were secondary to their differences in voltage-dependent gating, rather than being caused by direct effects of the mutation on the drug receptor. Together, these data show that a sodium channel mutation responsible for epilepsy can also alter channel response to antiepileptic drugs.

Animals↗

PubMed2006

Na channel gene mutations in epilepsy--the functional consequences.

Mutations of voltage-gated sodium channel genes SCN1A, SCN2A, and SCN1B have been identified in several types of epilepsies including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI). In both SCN1A and SCN2A, missense mutations tend to result in benign idiopathic epilepsy, whereas truncation mutations lead to severe and intractable epilepsy. However, the results obtained by the biophysical analyses using cultured cell systems still remain elusive. Now studies in animal models harboring sodium channel gene mutations should be eagerly pursued.

Action Potentials↗

PubMed2004

Flumazenil positron emission tomography and other ligands for functional imaging.

Most PET receptor studies in idiopathic generalized epilepsy conducted to date include only small numbers of patients and should be interpreted with caution. Differences between earlier and later studies can largely be explained by different inclusion criteria and improving methodology. The finding of some increase of GABAA receptor binding in IGE has a potential pathologic basis in microdysgenesis. Future studies aiming to elucidate the pathophysiology of IGEs may benefit from the use of subtype-specific opioid ligands, available now, and GABAB ligands, if and when they become available.

Brain↗

PubMed2005

A novel SCN1A mutation associated with severe GEFS+ in a large South American pedigree.

Generalized epilepsy with febrile seizures plus (GEFS+) is an inherited epileptic syndrome with a marked clinical and genetic heterogeneity. Here we report the molecular characterization of a large pedigree with a severe clinical form of GEFS+. Genetic linkage analysis implied the involvement of the FEB3 in the disease phenotype of this family (parametric two-point lod-score of 2.2). Sequencing of the SCN1A gene revealed a novel aspartic acid for glycine substitution at position 1742 of this sodium channel subunit. The amino-acid replacement lies in the pore-forming region of domain IV of SCN1A. Our observations are consistent with the genotype-phenotype correlation studies suggesting that mutations in the pore-forming loop of SCN1A can lead to a clinically more severe epileptic syndrome.

Adult↗

PubMed1986

[The good use of multivariate statistics].

Within a multidisciplinary team, it is important to establish a common language for the statistician and the electroencephalographer. Using an example, we propose a brief introduction to correspondence analysis. Within a set of 8 variables, we show how to isolate a subset of variables which are characteristic either for partial epilepsy or generalized epilepsy.

Adult↗

PubMed1996

Gabapentin in generalized seizures.

The efficacy of gabapentin (Neurontin), in generalized seizures was evaluated in this 14 week, double-blind, placebo-controlled, parallel-group, add-on, multicenter study. A total of 129 patients with refractory generalized seizures were randomized to receive either placebo or 1200 mg/day gabapentin as add-on therapy. Patients received their standard regimens of antiepileptic drugs (AEDs) during a 12 week baseline period, and gabapentin or placebo was added-on in the subsequent 14 week evaluation period. Results of both an intent-to-treat (ITT) and evaluable-patient analyses showed that gabapentin provided greater reduction in the frequency of generalized tonic-clonic seizures than did placebo; however, the differences between treatments were not statistically significant. Gabapentin did not affect the frequency of absence or myoclonic seizures. Adverse events were reported by 67% of gabapentin-treated patients and by 56% of placebo-treated patients. The most frequently occurring adverse events among patients receiving gabapentin were somnolence, fatigue, and dizziness. Gabapentin is well tolerated by patients with generalized seizures. The results of this study show a trend toward an effect of gabapentin in reducing the frequency of generalized tonic-clonic seizures and suggest that further exploration of high dose gabapentin in generalized epilepsy is warranted.

Acetates↗

PubMed1998

Long-term follow-up study of vigabatrin in pretreated children with West syndrome.

A multicentre, long-term, open-label, add-on study of vigabatrin was undertaken in 23 pretreated children with infantile spasms. After 3 months of vigabatrin therapy 11 of the 23 patients had become seizure-free. At this time two-thirds of these 11 children still received other antiepileptic drugs (AEDs) in addition to vigabatrin (mostly valproic acid and/or dexamethasone). After a mean follow-up time of 5 1/4 years (range: 4 1/4-6 1/2) 72% of 18 evaluable patients (two children died, three were lost to follow-up) revealed seizure freedom for at least 1 year. The mean duration of vigabatrin therapy had been 2 1/2 years (range: 2 weeks to 4 3/4 years). Two-thirds of the 18 children continued to take AEDs, three of them undergoing vigabatrin monotherapy. Relapses of infantile spasms had occurred in 14% of the children. The rate of vigabatrin side effects (10%) was low. At follow-up, the EEG of 13 and the 18 patients demonstrated focal or multifocal epileptic discharges. Fifty-five percent had developed another epilepsy (focal epilepsy, secondary generalized epilepsy or myoclonic-astatic epilepsy). With respect to mental functions, three children were normal or slightly retarded, four showed moderate retardation and 11 revealed severe or very severe retardation. This long-term result is comparable to that in ACTH studies with unselected patients. The conclusions are: (1) vigabatrin is an effective drug for the short-term and long-term treatment of refractory infantile spasms; (2) the relapse rate is low; (3) vigabatrin is well tolerated; (4) with respect to secondary epilepsies and mental functions the long-term outcome in these pretreated children is similar to that in earlier studies with ACTH or corticosteroids.

Adrenocorticotropic Hormone↗

PubMed2001

Simultaneous EEG and functional MRI of epileptic activity: a case report.

OBJECTIVES: Attempts to localize the source of epileptic activity by linking electroencephalographic (EEG) abnormalities to blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) signal alterations are hampered mainly by EEG distortions during MRI, subject motion, and unknown hemodynamic response characteristics. METHODS: Using T2*-weighted echo-planar imaging at 2.0 T (2 s temporal resolution, 2 x 2 x 4 mm(3) spatial resolution), this work demonstrates strategies to alleviate some of these problems while studying a patient who had ideopathic generalized epilepsy with poly-spike and slow-wave complexes. RESULTS: Continuous EEG recordings during dynamic MRI (500 ms scanning, 1500 ms delay) and post-examination derivation of an EEG reference function for MRI analysis revealed positive BOLD MRI responses with temporal characteristics similar to those obtained for functional challenges. CONCLUSIONS: The ability to map focal epileptic activity and/or associated cognitive processing provides new potential for both epilepsy research and clinical patient management.

Adult↗

PubMed2003

Callosal role in generation of epileptiform discharges: quantitative analysis of EEGs recorded in patients undergoing corpus callosotomy.

OBJECTIVE: Corpus callosotomy tends to decrease seizure frequency and severity rather than transforming the seizure pattern from a generalized form into a lateralized or a partial one. The finding implies that bisection of the corpus callosum (CC) disrupts the epileptogenicity itself. In order to gain further insight into the possible role played by the CC in intractable generalized epilepsy, quantitative analyses of long-term EEGs were performed. METHODS: Analyses were made of epileptiform discharges contained in the pre- and postoperative long-term EEGs in 7 patients who had an anterior callosotomy for intractable epilepsy. The duration, number, and amplitude of all epileptiform burst activities were measured and statistically analyzed. RESULTS: After callosotomy, the total number of epileptiform burst activities, mean duration, and the total number of spike discharges decreased significantly. The two hemispheres could be divided into dominant and non-dominant ones as to the quantity of the residual epileptiform discharges. CONCLUSIONS: Corpus callosotomy unevenly reduced preoperative epileptiform discharges in both hemispheres, suggesting a facilitatory role played by the callosal neurons that enables the asymmetrical epileptogenic susceptible state of the two hemispheres to develop bisynchronous and bisymmetrical epileptiform discharges. SIGNIFICANCE: Corpus callosotomy decreased the quantity of the epileptiform discharges, suggesting the transhemispheric facilitation of seizure mechanisms.

Cerebral Cortex↗

PubMed1998

Efficacy of topiramate.

In controlled clinical trials, topiramate (Topamax) has demonstrated efficacy in refractory patients with complex partial seizures and secondarily generalized tonic-clonic seizures. Approximately 45 percent of 534 patients had a > or = 50 percent reduction in seizure frequency. Limited open label trials have shown that topiramate has broad spectrum activity and may be effective in patients with primary generalized epilepsies. The efficacy of topiramate compares very favourably with the efficacy of other new antiepileptic drugs recently introduced.

Anticonvulsants↗

PubMed2004

Haplotype association analysis of discrete and continuous traits using mixture of regression models.

We present a regression-based method of haplotype association analysis for quantitative and dichotomous traits in samples consisting of unrelated individuals. The method takes account of uncertain phase by initially estimating haplotype frequencies and obtaining the posterior probabilities of all possible haplotype combinations in each individual, then using these as weights in a finite mixture of regression models. Using this method, different combinations of marker loci can be modeled, to find a parsimonious set of marker loci that are most predictive and therefore most likely to be closely associated with the a quantitative trait locus. The method has the additional advantage of being able to use individuals with some missing genotype data, by considering all possible genotypes at the missing markers. We have implemented this method using the SNPHAP and Mx programs and illustrated its use on published data on idiopathic generalized epilepsy.

Chromosome Mapping↗

PubMed2002

Molecular genetics of febrile seizures.

Febrile seizures are the most common form of convulsion, occurring in 2-5% of infants in Europe and North America and in 6-9% in Japan. In large families, the febrile seizure (FS) susceptibility trait is inherited by the autosomal dominant pattern with reduced penetrance. Two putative FS loci, FEB1 (chromosome 8q13-q21) and FEB2 (chromosome 19p13.3) have been mapped. A clinical subset of FS, termed generalized epilepsy with febrile seizures plus (GEFS+), was reported. In GEFS+ families, a mutation in the voltage-gated sodium channel beta1 subunit gene (SCN1B) at chromosome 19q13.1 and two mutations of the same alpha1 subunit gene (SCN1A) at chromosome 2q24 were identified. These loci are linked to febrile convulsions in large families. We conducted a genome-wide linkage search for FS in one large family with subsequent linkage confirmation in 39 nuclear families using nonparametric allele-sharing methods, and found a new FS susceptibility locus, FEB4 (chromosome 5q14-q15). In contrast to the FEB1, FEB2, and GEFS+ genetic loci, linkage to FEB4 was suggested in nuclear FS families, indicating that FEB4 may be the most common linkage locus in FS families.

Age Factors↗

PubMed2006

Massively multiplayer online role-playing game-induced seizures: a neglected health problem in Internet addiction.

As the Internet has become rapidly and widely integrated into society, Internet addiction has become a growing psychosocial problem. However, epileptic seizure, another out-of-the-ordinary health problem, is often neglected in this regard. Ten patients who experienced epileptic seizures while playing the newest genre of electronic games -- Massively Multiplayer Online Role-Playing Games (MMORPGs) -- were investigated. Patients were predominantly male young adults, and most of the events were generalized tonic-clonic seizures, myoclonic seizures, and absences. These patients should be categorized into idiopathic generalized epilepsies. Even though photosensitivity was an important factor, behavioral and higher mental activities also seemed to be significant seizure precipitants. Results demonstrated that MMORPG-induced seizures were not analogous to the ordinary video game-induced seizures. Significantly, an epileptic seizure warning did not always appear on the websites of MMORPGs and instructions for the software. While the prevalence of MMORPG-induced seizures remains unknown, it may exceed our expectations and impact our society. Not only for clinical neurologists but also for the primary physicians, educators, sociologists, and global online game publishers, there should be an awareness of this special form of reflex seizures in order to provide an appropriate health warning to MMORPG players.

Adolescent↗

PubMed2005

Mutation in the Na+ channel subunit SCN1B produces paradoxical changes in peripheral nerve excitability.

To determine the effect of an established mutation of the beta1 subunit of Na(+) channels on nerve excitability, studies were undertaken in patients diagnosed with generalized epilepsy with febrile seizures plus (GEFS+). Multiple nerve excitability measurements were used to investigate the membrane properties of sensory and motor axons in five patients (aged 18-55 years) who were currently experiencing no seizures and were not on anticonvulsants. There was no history of paraesthesiae, fasciculation or cramps to suggest hyperexcitability of peripheral nerve axons. The median nerve was stimulated at the wrist, and compound muscle action potentials (CMAPs) were recorded from abductor pollicis brevis and the antidromic compound sensory nerve action potential (CSAPs) from digit 2. Stimulus-response behaviour, strength-duration time constant, threshold electrotonus, current-threshold relationship and the recovery of excitability following a supramaximal conditioning stimulus were recorded using threshold tracking. Compared with normal controls (n = 29), the axons of patients were of higher threshold. CMAPs and CSAPs were relatively small, although individual values remained within the normal ranges. Refractoriness and relative refractory period (markers of transient Na(+) channel function) were significantly reduced in GEFS+ patients with established mutations in SCN1B (P < 0.05), and strength-duration time constants (dependent on persistent Na(+) conductances) were reduced. It is suggested that, in peripheral nerve axons, the mutation underlying GEFS+ reduces the number of functioning Na(+) channels at the node of Ranvier and that this rather than any change in gating of individual channels dominates axonal excitability in these patients.

Action Potentials↗

PubMed2004

Autosomal dominant early childhood seizures associated with chondrocalcinosis and a mutation in the ANKH Gene.

We describe the pattern of early childhood seizures within a family with autosomal dominant chondrocalcinosis (CCAL, which causes adult-onset arthritis). All affected family members with CCAL experienced seizures in early childhood, usually, but not always, associated with fever. Similarities exist to the syndrome of generalized epilepsy with febrile seizures plus (GEFS+). A mutation within the ANKH gene on chromosome 5p has been found previously in this family; other patients with familial CCAL (but without seizures) have mutations in the same gene. ANKH codes for a transmembrane protein involved in the regulation of extracellular pyrophosphate ion levels, although its precise mechanism of action remains unclear. It is highly expressed in the brain, and its expression may be influenced by seizure activity. The mutation within this family creates a premature initiation codon, adding four amino acids to the N-terminus of the protein. We postulate that this may lead to a gain of function, causing seizure susceptibility as well as chondrocalcinosis. Mutations within this gene may underlie other forms of genetic epilepsy and febrile seizures.

Arthritis↗

PubMed2004

Very fast rhythmic activity on scalp EEG associated with epileptic spasms.

PURPOSE: Very fast activity was investigated on the ictal EEGs of epileptic spasms to elucidate the pathophysiology of West syndrome (WS) and related disorders from a novel point of view. METHODS: The traces of scalp ictal EEG of spasms temporally were expanded in 11 patients whose clinical diagnosis was symptomatic WS in six, cryptogenic WS in two, Aicardi syndrome in one, and symptomatic generalized epilepsy after WS in the remaining two. Time evolution of averaged power spectra of the ictal fast activity also was analyzed in each patient. RESULTS: Rhythmic gamma activity with frequency ranging from 50 to 100 Hz was detected in a total of 345 of 537 spasms. Fast activity was seen bilaterally in nine patients, was lateralized to one hemisphere in another, and appeared independently on each hemisphere in the remaining infant with Aicardi syndrome. Power spectra showed a clear peak corresponding to spasm-associated gamma rhythm, with frequency centering approximately 65 Hz and ranging from 51 to 98 Hz. The morphology and spectral characteristics of ictal gamma rhythm were completely different from those of muscle activity or alternating current (AC) artifacts. CONCLUSIONS: Spasm-associated gamma activity was clearly detected on the scalp. This observation may provide a clue to the pathophysiology of spasms.

Cerebral Cortex↗

PubMed2004

Initiation of treatment and selection of antiepileptic drugs in childhood epilepsy.

PURPOSE: A retrospective study was carried out on 53 cases with childhood epilepsy to evaluate the validity of the initial selection of antiepileptic drug (AED). METHODS: We investigated the AEDs selected at the beginning of the treatment from the medical records of 53 untreated cases. A follow-up study was undertaken to evaluate the effects of the AEDs. In the second study, we investigated the AEDs of 10 cases with atypical benign partial epilepsy (ABPE), to clarify whether the initial AEDs selected for rolandic epilepsy were related to the appearance of ABPE. RESULTS: The AEDs used at the initial stage consisted of carbamazepine (CBZ), valproic acid (VPA), phenobarbital (PB), and vitamin B6. The main AEDs were CBZ and VPA for localization-related epilepsy, and VPA for generalized epilepsy. The initial selection of AEDs in 41 (85.4%) of 48 cases treated with AEDs were considered to be correct from the results of follow-up. We could not specify any AEDs that related to the appearance of ABPE. CONCLUSIONS: The selection of AED in this series was considered to be most appropriate. We proposed a criterion to determine whether to begin the AED treatment immediately at the initial seizure.

Adolescent↗

PubMed2005

Genetics of idiopathic epilepsies.

PURPOSE: To search for clues to molecular genetics of common idiopathic epilepsy syndromes. Genetic defects have been identified recently in certain inherited epilepsy syndromes in which the phenotypes are similar to those of common idiopathic epilepsies. METHODS: Mutations identified as the causes of inherited idiopathic epilepsies were reviewed. RESULTS: Mutations of the genes encoding two subunits of the neuronal nicotinic acetylcholine receptor were found in autosomal dominant nocturnal frontal lobe epilepsy. Mutations of two K(+)-channel genes were identified in benign familial neonatal convulsions. Mutations of the genes encoding several subunits of the voltage-gated Na(+)-channel and gamma-aminobutyric acid (GABA)(A) receptor also were identified as the underlying causes of various epilepsy syndromes, such as autosomal dominant epilepsy with febrile seizures plus, benign familial neonatal infantile seizures, and autosomal dominant juvenile myoclonic epilepsy. Mutations within the same gene may result in different epilepsy phenotypes. Thus, the Na(+) channel, GABA(A) receptor, and their auxiliaries may be involved in the pathogenesis of various types of epilepsy. Some forms of juvenile myoclonic epilepsy, idiopathic generalized epilepsy, and absence epilepsy may result from mutations of Ca(2+) channels. Mutations of the Cl(-) channel have been recently found to be associated with a certain type of epilepsy. The recent discovery that mutations of LGI1, a gene encoding a nonchannel molecule, are associated with autosomal partial epilepsy with auditory features may provide a new insight into our understanding of the genetics of idiopathic epilepsy. CONCLUSIONS: These findings suggest the involvement of brain channelopathies in the pathogenesis of certain types of idiopathic epilepsy.

Codon, Nonsense↗