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PubMed2001

Brainstem activates paroxysmal discharge in human generalized epilepsy.

In nine patients with generalized epilepsy of convulsive seizures, the excitability change of the brainstem was evaluated over the course of the interictal paroxysmal discharge (poly spike-and-wave complex, poly SWC). The evaluation was carried out by a sequential analysis of brainstem auditory evoked potentials (BAEPs) before and during one sequence of poly SWC. The characteristics of BAEPs, i.e. far-field evoked potentials, allowed the evaluation of the excitability change in the brainstem, which was not influenced by the cortical activity. The excitability in the ventral brainstem, measured with the parameters of wave-III, showed a biphasic fluctuation (deceleration--acceleration) before the onset of poly SWC (minima at -0.7+/-0.4 s). On the other hand, the excitability in the dorsal brainstem, measured with the parameters of wave-V, showed no significant difference over the course of poly SWC. The results suggest that the biphasic excitability change in the ventral brainstem is conveyed to the cortex through the ascending activating system. The excitability acceleration preceded by deceleration in the ventral brainstem probably synchronizes the cortical activity profoundly enough to produce poly SWC through the activation of intralaminar thalamic neurons.

Adolescent↗
PubMed2001

Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus.

Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by the presence of febrile and afebrile seizures. The first gene, GEFS1, was mapped to chromosome 19q and was identified as the sodium-channel beta1-subunit, SCN1B. A second locus on chromosome 2q, GEFS2, was recently identified as the sodium-channel alpha1-subunit, SCN1A. Single-stranded conformation analysis (SSCA) of SCN1A was performed in 53 unrelated index cases to estimate the frequency of mutations in patients with GEFS+. No mutations were found in 17 isolated cases of GEFS+. Three novel SCN1A mutations-D188V, V1353L, and I1656M-were found in 36 familial cases; of the remaining 33 families, 3 had mutations in SCN1B. On the basis of SSCA, the combined frequency of SCN1A and SCN1B mutations in familial cases of GEFS+ was found to be 17%.

Amino Acid Sequence↗
PubMed2003

Increased neuronal firing in computer simulations of sodium channel mutations that cause generalized epilepsy with febrile seizures plus.

Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial syndrome with a complex seizure phenotype. It is caused by mutations in one of 3 voltage-gated sodium channel subunit genes (SCN1B, SCN1A, and SCN2A) and the GABA(A) receptor gamma2 subunit gene (GBRG2). The biophysical characterization of 3 mutations (T875M, W1204R, and R1648H) in SCN1A, the gene encoding the CNS voltage-gated sodium channel alpha subunit Na(v)1.1, demonstrated a variety of functional effects. The T875M mutation enhanced slow inactivation, the W1204R mutation shifted the voltage dependency of activation and inactivation in the negative direction, and the R1648H mutation accelerated recovery from inactivation. To determine how these changes affect neuronal firing, we used the NEURON simulation software to design a computational model based on the experimentally determined properties of each GEFS+ mutant sodium channel and a delayed rectifier potassium channel. The model predicted that W1204R decreased the threshold, T875M increased the threshold, and R1648H did not affect the threshold for firing a single action potential. Despite the different effects on the threshold for firing a single action potential, all of the mutations resulted in an increased propensity to fire repetitive action potentials. In addition, each mutation was capable of driving repetitive firing in a mixed population of mutant and wild-type channels, consistent with the dominant nature of these mutations. These results suggest a common physiological mechanism for epileptogenesis resulting from sodium channel mutations that cause GEFS+.

Action Potentials↗
PubMed1999

Cortical excitability and recovery curve analysis in generalized epilepsy.

Seven untreated patients with idiopathic generalized epilepsy were studied with recovery curve analysis using transcranial magnetic stimulation and compared with 16 controls. Patients had a shorter period of inhibition of the test response following a conditioning stimulus and demonstrated a period of increased facilitation of the test response at interstimulus intervals of 200 to 300 msec, which was similar to the mean interdischarge interval of spike-wave activity on EEG. This provides further evidence of cortical hyperexcitability in idiopathic generalized epilepsy.

Adolescent↗
PubMedDate not supplied

[Electroencephalographic diagnosis of the idiopathic generalized epilepsies of childhood].

INTRODUCTION: The idiopathic generalized epilepsies of childhood form a heterogeneous group of epileptic syndromes, with certain clinical and electroencephalographic characteristics in common. From the onset, the seizures affect both cerebral hemispheres with generalized clinical expression and from the start there are bilateral electroencephalographic patterns during seizures. These epilepsies have no known causes, there is a genetic predisposition and relation to the age of onset. The electroencephalographic characteristics during and between seizures have points in common: the basal electroencephalographic activity is normal in all the epilepsies of this group, the paroxystic anomalies are generalized, synchronic and symmetrical, and are formed of bilateral discharges of spikes, multiple spikes, spikes and waves and multiple spikes and waves, with discharges at a frequency of 3 Hz or more. DEVELOPMENT: In this article we review the electroencephalographic characteristics during and between seizures of the idiopathic generalized epilepsies and epileptic syndromes of childhood, with particular emphasis on childhood absences, since we consider this to be the commonest and most representative of the idiopathic generalized epilepsies of infancy. CONCLUSIONS: We consider that the electroencephalographic aspects of epilepsies and the epileptic syndromes make up a factor of great importance as a help in confirmation in diagnosis.

Adolescent↗
PubMed1998

Worsening seizures after surgery for focal epilepsy due to emergence of primary generalized epilepsy.

Our patient underwent right anteromesial temporal resection at 17 years of age for intractable complex partial seizures due to hippocampal sclerosis, and then developed juvenile myoclonic epilepsy after a change in medication. Postoperative seizures ceased after a change to valproate monotherapy. Our patient reminds us to remain aware that generalized and focal epilepsy may coexist as an unusual cause for surgical failure. We feel that these patients may still be favorable candidates for epileptic surgery, as long as the focal epileptogenic zone is amenable to resection and the generalized epilepsy appears to be readily controllable.

Adolescent↗
PubMed2004

GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies.

A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177Ala variant which is heterozygously associated with generalized epilepsy with febrile seizures plus. We also report an Arg220His allele in GABRD which is present in the general population. Compared with wild-type receptors, alpha1beta2Sdelta GABAA receptors containing delta Glu177Ala or Arg220His have decreased GABAA receptor current amplitudes. As GABAA receptors mediate neuronal inhibition, the reduced receptor current associated with both variants is likely to be associated with increased neuronal excitability. Since delta subunit-containing receptors localize to extra- or peri-synaptic membranes and are thought to be involved in tonic inhibition, our results suggest that alteration of this process may contribute to the common generalized epilepsies.

Amino Acid Substitution↗
PubMed1999

Mapping and positional cloning of common idiopathic generalized epilepsies: juvenile myoclonus epilepsy and childhood absence epilepsy.

Among the 40 to 100 million persons with epilepsy worldwide and the 2 to 2.5 million persons with epilepsies in the United States, approximately 50% have generalized epilepsies. Among all epilepsies, the most common are juvenile myoclonus epilepsy (JME) with 10% to 30% of cases, childhood absence epilepsy (CAE) with 5% to 15% of cases, and pure grand mal on awakening with 22% to 37% of cases. In the last decade, six different chromosomal loci for common generalized epilepsies have been identified. These include two separate loci for JME in chromosomes 6p and 15q. The epilepsy locus in chromosome 6p expresses the phenotypes of classic JME, pure grand mal on awakening, and possibly JME mixed with absences. Two separate loci also are present for pyknoleptic CAE, namely, CAE that evolves to JME in chromosome 1p and CAE with grand mal in chromosome 8q24. Pandolfo et al. from the Italian League Against Epilepsy have reported two other putative susceptibility loci for idiopathic generalized epilepsies, namely, grand mal and generalized spike waves 35l in chromosome 3p and generalized epilepsies with febrile convulsions, grand mal, JME, absences, and electroencephalographic spike waves in 8q24. This chapter reports on the debate concerning whether there may be two separate epilepsy loci in chromosome 6p, one in the HLA region and one below HLA. The chapter then discusses the progress made in our laboratories as a result of the Genetic Epilepsy Studies (GENES) International Consortium. We discuss (a) the 2 to 6 cM critical region for classic JME located some 20 cM below HLA in chromosome 6p, (b) the 7-cM area for pyknoleptic CAE that evolves to JME in chromosome 1p, and (c) the 3.2 cM area for pyknoleptic CAE with grand mal and irregular 3 to 4 Hz spike waves in chromosome 8q24. We discusses efforts underway to refine the genetic map of JME in chromosome 6p11 and the advances in physical mapping and positioning of candidate genes, such as the gamma-aminobutyric acid receptor gene, the potassium channel gene of the long-QT family (KvLQT), named KCNQ3, and the human homologue of the mouse jerky gene for CAE in chromosome 8q24 and JME in chromosome 6p11.

Chromosome Mapping↗
PubMed2003

Magnetic resonance spectroscopy and imaging of the thalamus in idiopathic generalized epilepsy.

Experimental work in animal models of generalized epilepsy and clinical data in humans with idiopathic generalized epilepsy (IGE) indicate that the thalamo-cortical circuitry is involved in the generation of epileptic activity. The purpose of this study was to evaluate in vivo the chemical and structural integrity of the thalamus in patients with IGE. Thalamic proton magnetic resonance spectroscopic imaging (1H-MRSI), measuring N-acetylaspartate (NAA), choline-containing compounds and creatine (Cr) was performed in 20 IGE patients and in a group of age-matched healthy subjects. Additionally, 1H-MRSI measurements were taken in the insular cortex, the posterior temporal lobe white matter and the splenium of the corpus callosum. MRI volumetric analysis of the thalamus was performed in all patients. At the time of the examination, seizures were well controlled in 10 IGE patients and poorly controlled in nine. One patient was newly diagnosed and had the MRI and MRSI examination prior to starting the antiepileptic medication. In IGE patients, 1H-MRSI showed a reduction of mean thalamic NAA/Cr compared with normal controls; no difference was found in NAA/Cr in the other examined areas. There was no difference in NAA/Cr between patients whose seizures were well controlled and those in whom seizures were not controlled. There was no correlation between thalamic NAA/Cr and mean number of spike and wave complexes. We found a significant negative correlation between thalamic NAA/Cr and duration of epilepsy. The mean thalamic volume in patients with IGE was not different from normal controls. These results show evidence of progressive thalamic neuronal dysfunction in patients with IGE supporting the notion of abnormal thalamo-cortical circuitry as a substrate of seizure generation in this form of epilepsy. The thalamic dysfunction may occur regardless of amount of spike and wave activity.

Adult↗
PubMed1999

Observations on the misdiagnosis of generalized epilepsy as partial epilepsy: causes and consequences.

More therapeutic options (surgical and pharmacologic) are available for partial than for generalized epilepsies. This report describes and analyzes a possible bias to diagnose focal epilepsies. Data were prospectively collected on patients who underwent noninvasive prolonged EEG-video monitoring over a 2-year period at an epilepsy program. Cases where the diagnosis of 'partial seizures' (after monitoring) was questionable were identified and the data reviewed. Sixteen cases were identified. (a) Six had an idiopathic generalized epilepsy. All had generalized tonic-clonic (GTC) seizures, two had myoclonic seizures, and three had typical absences. All patients had generalized spikes and spike-wave complexes. All had normal IQs and normal brain imaging. One patient underwent invasive EEG. (b) Ten patients had a symptomatic or cryptogenic generalized epilepsy. IQs ranged from 49 to 74 (mean: 63). All patients had diffuse EEG slowing, and generalized ictal EEG patterns. Interictal EEG showed generalized spike-wave complexes in nine, and multifocal spikes in five. Seizures included GTC in all, generalized tonic in four, and atypical absences in two. Two of the 10 patients underwent invasive EEG. The misdiagnosis of generalized epilepsy as partial epilepsy occurs for both idiopathic and cryptogenic or symptomatic generalized epilepsies, more often in the latter case. Risk factors may include: asymmetry in EEG or seizure semeiology, the eagerness to enroll in drug studies or surgical programs, and the lack of team thinking involving several epileptologists. This problem is almost certainly under-reported and may occasionally result in unwarranted invasive procedures.

Adolescent↗
PubMed1985

[Clinical features of generalized epilepsy].

The pattern of generalized seizures was studied in 75 patients with the primary, mixed and secondary forms of generalized epilepsy. The majority of the patients (n-52) presented with generalized seizures with a complex development of generalized and partial motor disturbances throughout the entire paroxysm. The disturbances were divided into 3 variants. Referred to the first variant are convulsive manifestations in the structure of grand mal epilepsy when, in the presence of bilateral convulsions, they were predominant in the facial muscles on one side or muscles of the anterior or posterior aspect of the body. If generalized seizures were more predominant on one side, such motor disorders were attributed to the 2nd variant. The 3rd variant of generalized epileptic seizures was characterized by asymmetric convulsions.

Abdomen↗
PubMed2002

Nonsymptomatic generalized epilepsy in children younger than six years: excellent prognosis, but classification should be reconsidered after follow-up: the Dutch Study of Epilepsy in Childhood.

PURPOSE: To assess the prognosis and the accuracy of the epilepsy classification in young children with nonsymptomatic generalized epilepsy. METHODS: Of the cohort of the Dutch Study of Epilepsy in Childhood (n = 466), all children younger than 6 years with a diagnosis of idiopathic (IGE) or cryptogenic (CGE) generalized epilepsy either at intake (n = 108) and/or after 2 years of follow-up (n = 102) were included. The number of reclassifications after 2 years was determined, and the reasons for reclassification were analyzed. All children receiving a diagnosis of IGE or CGE at 2 years were followed up for 5 years to study their outcome in terms of terminal remission (TR). Data on their level of intellectual functioning were collected at the start of this analysis. RESULTS: The epilepsy syndrome was reclassified in 17 children. In 14 of them, the seizure type also was reclassified, and in three, the course of the epilepsy determined the new epilepsy type. Two other children had a reclassification of their seizure types without a change of the epilepsy type. Many children were categorized as having IGE not otherwise specified. In all probability, this is a heterogeneous group, containing patients with various epilepsy syndromes, with generalized tonic-clonic seizures as a common hallmark. Of the 102 children with IGE or CGE at 2 years of follow-up, 75% had a TR of >6 months after 2 years, and 85% a TR of >or=1 year after 5 years. CONCLUSIONS: In a fair proportion of children with nonsymptomatic generalized epilepsy in this age group, it is not possible to classify firmly the epilepsy and/or the seizures immediately after the intake. Instead, they are reclassified during the course of the disease. This and the apparent heterogeneity of the category IGE not otherwise specified point to inherent drawbacks of the current International League Against Epilepsy (ILAE) classification of epilepsy and epileptic syndromes. The prognosis of IGE at this young age is generally excellent.

Age Factors↗
PubMed2006

MRI reveals structural abnormalities in patients with idiopathic generalized epilepsy.

OBJECTIVE: To evaluate MRI findings in a large group of patients with idiopathic generalized epilepsies. METHODS: Idiopathic generalized epilepsies were diagnosed according to clinical and EEG criteria following International League Against Epilepsy recommendations. MRI was performed in a 2.0 T scanner using a previously established epilepsy protocol. Images were reviewed, and any abnormality was reported. Patients were divided in those with and without MRI abnormalities. Comparisons were made between these groups concerning age, age at seizure onset, subsyndrome, EEG findings, and seizure control. RESULTS: Of the 134 MRIs evaluated, 33 (24%) showed abnormalities, most of which (88%) were nonspecific. There were eight main abnormalities: arachnoid cyst, diffuse cortical atrophy, basal ganglia abnormalities (signal alterations and prominent perivascular spaces), ventricular abnormalities (uni- or bilateral increased volume of the lateral ventricles), white matter abnormalities (increased T2 signal in the frontal lobes), reduced hippocampal volume, focal gyral abnormality, and area of gliosis in the frontal lobe. Comparisons between the groups showed a higher proportion of EEG focalities in patients with abnormal MRI, which were in most part concordant with the location of the MRI abnormalities. CONCLUSIONS: Twenty-four percent of patients with idiopathic generalized epilepsies had MRI abnormalities. However, the majority of these abnormalities were nonspecific.

Adolescent↗
PubMed2006

Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy.

Aggravation of idiopathic generalized epilepsy (IGE) syndromes by inappropriate antiepileptic drugs (AEDs) is increasingly recognized as a serious and common problem. Precipitation of status epilepticus (SE) by inappropriate medication has rarely been reported. We retrospectively studied all adult patients with IGE taking at least one potentially aggravating AED, who developed video-EEG documented SE over 8 years, and whose long-term outcome was favourable after adjustment of medication. We identified 14 patients (seven male patients) aged 15-46 years with a mean duration of epilepsy of 16.4 years. Video-EEG demonstrated typical absence SE (ASE) in five, atypical ASE in five, atypical myoclonic SE (MSE) in three and typical MSE in one. Epilepsy had been misclassified as cryptogenic partial in eight cases and cryptogenic generalized in four. The correct diagnosis proved to be juvenile absence epilepsy (JAE) in six patients, juvenile myoclonic epilepsy (JME) in four, epilepsy with grand mal on awakening (EGMA) in two and childhood absence epilepsy (CAE) in two. All patients had been treated with carbamazepine (CBZ) and had experienced seizure aggravation or new seizure types before referral. Seven patients had polytherapy with phenytoin (PHT), vigabatrin (VGB) or gabapentin (GBP). Potential precipitating factors included dose increase of CBZ or of CBZ and PHT; initiation of CBZ, VGB or GBP; and decrease of phenobarbital. Withdrawal of the aggravating agents and adjustment of medication resulted in full seizure control. This series shows that severe pharmacodynamic aggravation of seizures in IGE may result in ASE or MSE, often with atypical features.

Adolescent↗
PubMed2004

MRS shows syndrome differentiated metabolite changes in human-generalized epilepsies.

OBJECTIVE: While it is generally accepted that the thalamo-cortical loop is abnormal in idiopathic generalized epilepsy (IGE), it is uncertain whether this loop is similarly affected among different IGE syndromes. We recently demonstrated reduced frontal lobe levels of N-acetyl aspartate (NAA) in patients with juvenile myoclonic epilepsy (JME). The present follow-up study investigates if similar or other types of changes exist in subjects with pure primarily generalized tonic clonic epilepsy (GTCS). METHOD: Twenty patients with GTCS, 26 patients with JME, and 10 matched healthy controls were investigated with quantitative single voxel MR spectroscopy (MRS) measurements of NAA, choline (Cho), creatine (Cr), and myo-inositol (mI) at 1.5 T scanner. The voxels were placed over the right cerebellum, right thalamus, prefrontal, occipital cortex, and over a spherical phantom above the subject's head. RESULTS: Patients with JME had reduced frontal lobe NAA (mmol/l) in relation to controls (9.8 +/- 1.1 vs. 10.8 +/- 0.7, P = 0.01), as well as GTCS patients (9.8 +/- 1.1 vs. 10.6 +/- 0.7, P = 0.007), whose values were normal. Patients with GTCS, on the other hand, showed significantly lower thalamic NAA than controls (9.7 +/- 1.0 vs. 10.8 +/- 0.9, P = 0.002), and both groups of patients had reduced thalamic Cho, and mI; [CHO: 2.0 +/- 0.4 (control) vs. 1.61 +/- 0.3 (JME) P = 0.001, and vs. 1.57 +/- 0.3 (GTCS) P = 0.0005; MI: 4.8 +/- 1.5 (control) vs. 3.3 +/- 1.4 (JME) P = 0.003, and vs. 3.2 +/- 1.5 (GTCS), P = 0.002]. No other regional changes were observed. CONCLUSION: The present MRS data emphasize the involvement of thalamus in IGE. They also show partly differentiated alterations within the thalamo-cortical loop in JME vs. GTCS. The various clinical expressions of IGE may, thus, be associated with more localized neuroanatomical substrates than generally believed.

Adolescent↗
PubMed2001

Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy.

Genetic predisposition plays a major role in the etiology of idiopathic epilepsies. The common epilepsy syndromes display a complex pattern of inheritance, with an unknown number of genes contributing to seizure susceptibility. During the last decade linkage studies have narrowed down several candidate regions for susceptibility loci of idiopathic epilepsies. Several lines of evidence point to the existence of an epilepsy susceptibility gene on chromosome 15q14. Evidence for linkage to this region has thus been reported for juvenile myoclonic epilepsy, common subtypes of idiopathic generalized epilepsy (IGE), in addition to the EEG trait 'centrotemporal spikes' in families with rolandic epilepsy. The chromosomal region 15q14 harbours several candidate genes that are involved in the regulation of neuronal excitability. One of the most promising candidate genes is the brain-expressed potassium chloride cotransporter KCC3, given that this class of ion transporter has been implicated in the regulation of neuronal chloride activity. We therefore performed a mutation analysis of KCC3 in the index patients of 23 IGE-families as well as of 16 families with rolandic epilepsy which where selected by positive evidence for linkage to D15S165. Four novel single nucleotide exchanges (SNPs) were identified, none of which change the coding sequence. These results do not support a major role for KCC3 in the etiology of rolandic epilepsy or common subtypes of IGE.

Carrier Proteins↗